Pharmaceutical compositions of mifepristone

ABSTRACT

Pharmaceutical compositions and stable nano-suspensions comprising mifepristone and at least one pharmaceutically acceptable excipient, which exhibit enhanced bioavailability compared to the currently marketed or commercially available formulations. Manufacturing process and methods of use are also provided. The pharmaceutical compositions are used for prevention, treatment or prophylaxis of disorders in human patients in need thereof. Oral pharmaceutical compositions of mifepristone, methods for their administration, processes for thei r production, and use of these compositions are described for the treatment of diseases for which mifepristone is indicated.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims foreign priority to Indian Application No. IN202141040290, filed on Sep. 6, 2021, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions comprisingmifepristone, which is a glucocorticoid antagonist, and at least onepharmaceutically acceptable excipient, wherein the inventivepharmaceutical compositions exhibit enhanced bioavailability compared toa reference drug product, such as the currently marketed or commerciallyavailable formulations. The present invention further providesmanufacturing process and use of the inventive compositions for theprevention, treatment or prophylaxis of disorders in human patients inneed thereof.

In particular, the present invention relates to oral pharmaceuticalcompositions and stable nano-suspensions of mifepristone particles,methods for their administration, processes for their production, anduse of these compositions for treatment of diseases treatable bymifepristone.

BACKGROUND OF THE INVENTION

Mifepristone is a potent antagonist of steroid hormone receptors such asglucocorticoid, progesterone and androgen receptors. Mifepristone is aselective antagonist of the progesterone receptor at low doses andblocks the glucocorticoid receptor at higher doses. Mifepristone is usedfor termination of pregnancy and to treat disorders like Cushing'ssyndrome and different types of proliferative disorders. The chemicalname of mifepristone is11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(1-propynyl)-estra-4,9-dien-3-one. The structural formula is:

Mifepristone is currently marketed under the brand name KORLYM® (300 mg;National Drug Code Number 76346-073; NDA 202107).

KORLYM® is available in the form of film-coated tablets containing 300mg of mifepristone. KORLYM® film-coated tablets (300 mg; National DrugCode Number 76346-073; NDA 202107) contain inactive ingredients such assilicified microcrystalline cellulose, sodium starch glycolate,hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate,hypromellose, titanium dioxide, triacetin, D&C yellow 10 aluminum lake,polysorbate 80, and FD&C yellow 6 aluminum lake. KORLYM® is used totreat high blood sugar (hyperglycemia) caused by high cortisol levels inthe blood (hypercortisolism) in adults with endogenous Cushing'ssyndrome who have type 2 diabetes mellitus or glucose intolerance andhave failed surgery or cannot have surgery.

Cushing's syndrome of endogenous origin is a hormonal disease associatedwith an increased blood concentration of cortisol (hypercortisolism) orthe presence in blood of glucocorticoid hormone excess over a longperiod of time. Cushing's syndrome is classified as either ACTHdependent or non-ACTH dependent.

Adrenocorticotropic hormone (ACTH) dependent Cushing's syndrome ischaracterized by a chronic ACTH hypersecretion which stimulates thegrowth of the adrenal glands and the hypersecretion of corticosteroids.The most common underlying cause of ACTH dependent Cushing's syndrome isexcessive production of ACTH by pituitary adenomas. Cushing's syndromeresulting from the production of ACTH in another location than thepituitary gland is known as ectopic Cushing's syndrome. Examples ofectopic sites include thymoma, medullary carcinoma of the thyroid,pheochromocytoma, islet cell tumors of the pancreas and small cellcarcinoma of the lung.

The package insert of KORLYM® discloses that the patients are instructedto take the tablet once daily with a meal. The daily dose of KORLYM® maybe increased in 300 mg increments. The dose of KORLYM® may be increasedto a maximum of 1200 mg once daily but should not exceed 20 mg/kg perday. Increases in dose should not occur more frequently than once every2-4 weeks. Decisions about dose increases should be based on a clinicalassessment of tolerability and degree of improvement in Cushing'ssyndrome manifestations. Changes in glucose control, anti-diabeticmedication requirements, insulin levels, and psychiatric symptoms mayprovide an early assessment of response (within 6 weeks) and may helpguide early dose titration.

Following oral administration, time to peak plasma concentrations ofmifepristone occurs between 1 and 2 hours following single dose, andbetween 1 and 4 hours following multiple doses of 600 mg of KORLYM® inhealthy volunteers.

Mean plasma concentrations of three active metabolites of mifepristonepeak between 2 and 8 hours after multiple doses of 600 mg/day, and thecombined concentrations of the metabolites exceed that of the parentmifepristone. Exposure to mifepristone is substantially less than doseproportional. Time to steady state is within 2 weeks, and the mean (SD)half-life of the parent mifepristone was 85 (61) hours followingmultiple doses of 600 mg/day of KORLYM®.

Mifepristone is primarily metabolized by N-demethylation and terminalhydroxylation of the 17-propynyl chain of mifepristone. In-vitro studieshave shown that CYP450 3A4 is primarily responsible for metabolism. Thethree major metabolites identified in humans are: (1) RU42633, the mostwidely found in plasma, is the N-mono-demethylated metabolite; (2)RU42848, which results from the loss of two methyl groups from the4-dimethylaminophenyl in position 11β, and (3) RU42698, which resultsfrom terminal hydroxylation of the 17-propynyl chain.

Peak mean plasma concentrations of three active metabolites ofmifepristone were attained between 2 and 8 hours after multiple doses of600 mg/day, and the combined concentrations of the metabolites exceedthat of the parent mifepristone. Time to attain steady state is within 2weeks, and the mean half-life of the parent mifepristone was 85 hoursfollowing multiple doses of 600 mg/day of KORLYM®. KORLYM® demonstratesa significant increase in plasma levels of mifepristone when dosed withfood.

The drug absorption after oral administration generally depends on (i)the release of the drug from the composition, (ii) the dissolution ofthe drug under physiological conditions and (iii) its permeabilityacross the gastrointestinal tract. A higher dissolution rate of acomposition generally increases release of the drug from itscomposition, which is a prerequisite for adequate bioavailability of adrug. Because of this requirement, a good in vitro dissolution of thecomposition may lead to good and adequate in vivo plasma concentrationand therefore an adequate bioavailability.

Mifepristone is very soluble in methanol, chloroform and acetone andpractically insoluble in water. Mifepristone demonstrates a pH-relatedsolubility profile. Solubility of mifepristone is dramatically high inacid (˜25 mg/mL at pH 1.5) and declines rapidly as pH increases (i.e.,above pH 2.5 the solubility of mifepristone is less than 1 mg/mL).Mifepristone is poorly water soluble and hence, it would be difficult toformulate and deliver oral dosage forms which exhibit goodbioavailability.

Mifepristone is characterized as a Biopharmaceutical ClassificationSystem (BCS) class IV compound, which means that it has low aqueoussolubility and low permeability. For BCS class IV drugs likemifepristone, the dissolution step is the rate-determining factor indrug absorption. Current strategies employed to improve the apparentsolubility of a drug include the use of: (i) co-solvents (e.g., lowmolecular weight polyethylene glycols and propylene glycol) incombination with water to dissolve the drug; (ii) complexing agents(e.g., cyclodextrins and its derivatives) to form water-solubleinclusion complexes of the drug or (iii) hydrophilic excipients (e.g.,polyvinylpyrrolidones and high molecular weight polyethylene glycols) asdrug carriers for the preparation of solid dispersions in which the drugis dispersed molecularly or as ultrafine crystals. However, drugprecipitation is a common problem faced by these formulations. The drugstend to precipitate in vivo due to a sudden pH change from stomach tointestine, formulation dilution by body fluids, or digestion ofsolubilizing excipients in formulations. Such precipitation usuallyleads to a low oral bioavailability with a delayed response or reducedefficacy. As a result, in vivo drug precipitation poses a greatchallenge for the development of oral formulations and dosage formdevelopment.

The need for administering such high doses of mifepristone may be due tothe low bioavailability exhibited by KORLYM® and may be responsible forthe adverse side effects associated with the use of mifepristone such asnausea or emesis, dizziness and diarrhea. Moreover, low bioavailabilityresults in more variable absorption and potential variability of thedesired therapeutic response.

Thus, there exists a need to develop pharmaceutical compositions ofmifepristone, which increase the bioavailability of mifepristone,thereby reducing the dose of mifepristone which must be administered toa human subject for a therapeutic effect, and resulting in reducedadverse events and enhanced patient safety.

SUMMARY OF THE INVENTION

The present invention addresses this need by providing pharmaceuticalcompositions comprising mifepristone and at least one pharmaceuticallyacceptable excipient, wherein the inventive pharmaceutical compositionsexhibit enhanced bioavailability compared to the currently marketed orcommercially available formulations. Due to the increasedbioavailability or absorption, the dosage according to the invention canbe lower than the usual or the conventional dose typically required toproduce equal or higher therapeutic effect, and may also reduce the sideeffects and limit the risk to the patient.

The present invention also provides compositions to improve thebioavailability of mifepristone in the fed state and provide acomposition which maintains optimal therapeutic concentrations ofmifepristone in the human subject, and at the same time reduces the sideeffects exhibited by the same.

In certain embodiments, the compositions for oral administrationaccording to the present invention provide mifepristone to a patientpopulation with lower variability in bioavailability, thus providingconsistent pharmacokinetic parameters (e.g., a narrower observed rangefor C_(max) and AUC values) across patient population to whom thecomposition is administered.

The pharmaceutical compositions of mifepristone according to theinvention, upon oral administration, provide enhanced bioavailability ofmifepristone in the fed or fasted state compared to a reference drugproduct. As used herein, the reference drug product, is a currentlymarketed or commercially available formulation. In certain embodiments,the KORLYM® drug product (National Drug Code Number 76346-073; NDA202107), available as a 300 mg tablet, is the reference composition. Theincrease in oral bioavailability may enable administration ofmifepristone at a significantly lower therapeutically effective dosesthan what are currently being used.

The compositions of mifepristone according to the invention are suitablefor oral administration to patients, and can provide uniform plasmalevel(s) and sufficient mifepristone exposure (AUC) in fasted and fedstate when compared to commercially available formulation (e.g.,KORLYM®). Also, the inventive oral compositions of mifepristone, whenadministered to a human subject, exhibit less variability inpharmacokinetic parameters (e.g., C_(max), AUC_(0-t) and/orAUC_(0-infinity)) than a commercially available reference mifepristoneformulation of the same dosage (e.g., KORLYM®).

The composition of mifepristone according to the invention providestable pharmaceutical compositions of mifepristone suitable for oraladministration, exhibiting improved solubility and increasedbioavailability of mifepristone when compared to the commerciallyavailable reference drug product (such as KORLYM®), wherein thecomposition remains stable for at least 6 months at 40° Cs/75% RH(“relative humidity”) or 25° C./60% RH (“relative humidity”).

The inventive compositions for oral administration provide enhancedbioavailability of mifepristone in the fed and/or fasted states comparedto commercially available reference formulation, e.g., KORLYM®. In anaspect, the present invention relates to inventive compositioncomprising mifepristone suitable for oral administration, wherein saidcomposition exhibits enhanced bioavailability in the fed state, comparedto commercially available product (KORLYM®).

In an aspect, the dose of inventive pharmaceutical compositioncomprising mifepristone is reduced by at least 10% in comparison tocommercially available product (KORLYM®). In one aspect, thepharmaceutical compositions may exhibit at least about 15% enhancedbioavailability in the fed state, compared to a drug productcorresponding to a reference composition having the same dosage.

In another aspect, the dose of inventive pharmaceutical compositioncomprising mifepristone is reduced by at least 20% in comparison tocommercially available product (KORLYM®). In another aspect, the dose ofinventive pharmaceutical composition comprising mifepristone is reducedby at least 30% in comparison to commercially available product(KORLYM®). In another aspect, the dose of inventive pharmaceuticalcomposition comprising mifepristone, is reduced by at least 50% incomparison to commercially available product (KORLYM®). In anotheraspect, the dose of inventive pharmaceutical composition comprisingmifepristone, is reduced by at least 75% in comparison to commerciallyavailable product (KORLYM®).

In an aspect, the inventive pharmaceutical composition comprisingmifepristone exhibits less variability in pharmacokinetic parameters(C_(max), AUC_(0-t) and/or AUC_(0-infinity)) compared to a commerciallyavailable reference product (such as KORLYM®), when administered orallyto human subjects.

In an aspect, the present invention relates to nano-suspensioncompositions of mifepristone. The present invention further relates tostable pharmaceutical composition for oral administration comprising thenano-suspension compositions of mifepristone.

In an aspect, the invention relates to a pharmaceutical compositioncomprising a therapeutically effective amount of mifepristone particlesand at least one pharmaceutically acceptable excipient, wherein themifepristone particles have an average D90 particle size equal to orless than about 1000 nm. In another aspect, the invention relates tostable nano-suspensions comprising: (a) a therapeutically effectiveamount of nano-sized mifepristone particles; and (b) at least onesuspension-aid, wherein the nano-sized mifepristone particles have anaverage D90 particle size equal to or less than about 1000 nm.Preferably, the stable nano-suspensions further comprising at least onesurfactant. For instance, the stable nano-suspensions may comprise orconsist of: (a) nano-sized mifepristone; (b) a suspension-aid comprisinghydroxypropyl methylcellulose; and (c) a surfactant comprising sodiumlauryl sulphate and (d) surface stabilizer comprising docusate sodium.

The pharmaceutical compositions and the stable nano-suspensions, mayhave at least one pharmaceutically acceptable excipient thatcomprises:(a) at least one suspension-aid; (b) at least one surfactant;and (c) optionally, one or more other pharmaceutically acceptableexcipients. Preferably, the at least one suspension-aid is selected fromthe group consisting of hydroxypropyl methyl cellulose acetate succinate(HPMC-AS), polyvinyl pyrrolidine and vinyl acetate (PVP/VA) copolymer,hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), hydroxypropylcellulose (HPC), carboxymethyl cellulose (CMC), polyvinyl pyrrolidine(PVP), and mixtures thereof. Preferably, the at least one surfactant issodium lauryl sulphate.

In other aspect, the present invention also relates to methods formaking nano-suspension of mifepristone, methods for preparingpharmaceutical composition, and methods for treating disorders using theinventive pharmaceutical composition.

In an aspect, the inventive pharmaceutical composition suitable for oraladministration to a human subject in need thereof, comprisesnano-suspension of mifepristone; wherein said composition exhibitsenhanced bioavailability in the fed state compared to commerciallyavailable reference product (such as KORLYM®).

In an aspect, the inventive pharmaceutical composition suitable for oraladministration to a human subject in need thereof, comprisesnano-suspension of mifepristone; wherein said composition exhibitsenhanced bioavailability in the fasted state compared to commerciallyavailable product (such as KORLYM®).

In another aspect, the pharmaceutical composition suitable for oraladministration to a human subject in need thereof, comprises anano-sized mifepristone, wherein the composition remains stable for atleast 6 months at 40° C./75% RH (“relative humidity”) or 25° C./60% RH(“relative humidity”).

Each of the aspects described in this application may further have oneor more of the following additional elements in any combination:

Element 1: the nano-suspension of mifepristone may comprise apharmaceutically acceptable suspension-aid.

Element 2: the nano-suspension of mifepristone may comprise at least onepharmaceutically acceptable suspension-aid, at least one surfactantand/or at least one surface stabilizer.

Element 3: the nano-suspension of mifepristone may comprise at least onesuspension-aid, at least one surfactant, at least one surface stabilizerand optionally one or more pharmaceutically acceptable excipient.

Element 4: the nano-suspension of mifepristone may be prepared by wetmedia milling process.

Element 5: the nano-particles have a mean diameter selected from thegroup consisting of a mean diameter of less than about 1000 nm,preferably less than 800 nm.

Element 6: the nano-suspension of mifepristone may have a weight ratioof the mifepristone to the pharmaceutically acceptable suspension-aidfrom about 1:1 to about 20:1. The amount of the at least one surfacestabilizer is preferably from about 0.05% w/w to about 1% w/w of a totalweight of the pharmaceutical composition, e.g., an amount of the atleast one surface stabilizer may be from about 0.05% w/w to about 1% w/wof a total core table weight.

Element 7: the nano-suspension of mifepristone may comprise at least onesuspension-aid selected from hydroxypropyl methyl cellulose acetatesuccinate (HPMC-AS), polyvinyl pyrrolidine and vinyl acetate (PVPNA)copolymer, hydroxypropyl methylcellulose phthalate (HPMCP),hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG),hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), polyvinylpyrrolidine (PVP), and mixtures thereof.

Element 8: the nano-suspension of mifepristone may comprise at least onesurfactant (for example, but not limited to sodium lauryl sulphate).

Element 9: the nano-suspension of mifepristone may further comprise oneor more pharmaceutically acceptable excipients selected from the groupconsisting of diluents, binders, disintegrants, lubricants, glidants,surfactants, solubilizers, plasticizers, surface stabilizers,antioxidants and combinations thereof.

Element 10: the inventive pharmaceutical compositions may comprise fromabout 100 mg to about 1200 mg of mifepristone, preferably about 240 mg.

Element 11: the inventive pharmaceutical compositions may preferably bein the form of a tablet, a capsule, a caplet, beads, granules, powder ororal suspension.

Element 12: the inventive pharmaceutical compositions may furthercomprise one or more pharmaceutically acceptable excipients selectedfrom the group consisting of diluents, binders, disintegrants,lubricants, glidants, surfactants, plasticizers, solubilizers, surfacestabilizers, antioxidants and combinations thereof.

Element 13: the inventive pharmaceutical compositions may preferably beobtained by direct compression, wet granulation or dry granulation.

Element 14: the inventive pharmaceutical compositions may preferably bein the form of a tablet or capsule comprising: (a) nano-sizedmifepristone (b) at least one intra-granular material, (c) at least oneextra-granular material, and (d) optionally, coating. In certainaspects, in the pharmaceutical compositions (a) the at least oneintra-granular material is selected from the group consisting ofsilicified microcrystalline cellulose, sodium starch glycolate, andmixtures thereof, and (b) the least one extra-granular material isselected from the group consisting of microcrystalline cellulose, sodiumstarch glycolate, colloidal silicon dioxide, magnesium stearate, andmixtures thereof.

Element 15: the inventive pharmaceutical compositions may preferably bein the form of a tablet comprising: the nano-suspension of mifepristonecan be sprayed over or mixed with at least one intra-granular material.

Element 16: the inventive pharmaceutical compositions may preferably bein the form of a tablet comprising: the nano-suspension of mifepristonecan be sprayed over or mixed with at least one intra-granular material,wherein intra-granular material contains one or more of the followingexcipients selected from the group consisting of diluents, binders,disintegrants, lubricants, glidants, surfactants, plasticizers,solubilizers, surface stabilizers, antioxidants and combinationsthereof.

Element 17: the inventive pharmaceutical composition preferably has thelevel of total related substances that is less than about 5% (w/w),preferably less than about 4% (w/w), preferably less than about 3%(w/w), preferably less than about 2% (w/w), preferably less than about1% (w/w) preferably less than about 1.5% (w/w) and more preferably lessthan about 0.5 (w/w) as measured by HPLC, when stored at 25° C./60% RHfor at least 3 months.

Element 18: the inventive pharmaceutical composition preferably has alevel of any unknown impurity that is less than about 1% (w/w),preferably less than about 0.5% (w/w), preferably less than about 0.25%(w/w), preferably less than about 0.15% (w/w) and more preferably lessthan about 0.1% (w/w) as measured by HPLC, when stored at 25° C./60% RHfor at least 3 months.

Element 19: the inventive pharmaceutical compositions for oraladministration exhibits faster dissolution rate of mifepristone comparedto commercially available reference formulation (such as KORLYM®).

Element 20: the inventive pharmaceutical compositions for oraladministration provides enhanced bioavailability of mifepristone infasting or fed state compared to commercially available referenceformulation (such as KORLYM®).

Element 21: the inventive pharmaceutical compositions for oraladministration provides enhanced bioavailability of mifepristone infasting and fed states which in turn reduces the dose of mifepristonewhich can be administered to a human subject compared to commerciallyavailable reference formulation (such as KORLYM®).

Element 22: the inventive mifepristone compositions may preferably beused in a method for treating proliferative disorder in a human subject,which method comprises: (a) providing a pharmaceutical composition; and(b) providing instructions for oral administration of the compositionindicating that the composition can be administered to a human subjectwith food.

Element 23: in the inventive pharmaceutical compositions, at least 50%of the mifepristone is released after about 30 minutes as determinedusing USP Apparatus II at 50 RPM in pH 1.8 KCl buffer 900 mL dissolutionmedia at 37° C.

Element 24: in the inventive pharmaceutical compositions, at least 70%of the mifepristone is released after about 45 minutes as determinedusing USP Apparatus II at 50 RPM in pH 1.8 KCl buffer 900 mL dissolutionmedia at 37° C.

Element 25: in the inventive pharmaceutical compositions, at least 50%of the mifepristone is released after about 30 minutes as determinedusing USP Apparatus II at 75 RPM in 0.01 N HCL 900 mL dissolution mediaat 37° C.

Element 26: the nano-suspension of mifepristone may have a weight ratioof the mifepristone to the pharmaceutically acceptable suspension-aidfrom about 20:1 to about 1:20.

Element 27: the nano-suspension of mifepristone may have a weight ratioof the mifepristone to surfactant from about 50:1 to about 1:50. Theamount of the at least one surface stabilizer is preferably from about0.05% w/w to about 1% w/w of a total weight of the pharmaceuticalcomposition, e.g., an amount of the at least one surface stabilizer maybe from about 0.05% w/w to about 1% w/w of a total core table weight.

Element 28: a pharmaceutical composition comprising an effective amountof the stable nano-suspension according to the invention, together witha pharmaceutically acceptable carrier, excipient or diluent.

Element 29: a method of treatment for Cushing's syndrome, or the use ofa pharmaceutical composition as defined herein for the manufacture of amedicament for the treatment of Cushing's syndrome. In an aspect, theinventive pharmaceutical compositions are used in a method of treatmentor for the manufacture of a medicament for the treatment of high bloodsugar (hyperglycemia) caused by high cortisol levels in the blood(hypercortisolism) in adults with endogenous Cushing's syndrome who havetype 2 diabetes mellitus or glucose intolerance and have failed surgeryor cannot have surgery.

By way of non-limiting examples, exemplary combinations applicable tothe embodiments described in this application may include anycombination with one or more of the elements described above.

By way of non-limiting example, exemplary combinations applicable to theembodiments described in this application may include any combinationwith one or more of the elements described above.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all the technical and scientific terms usedherein have the same meanings as commonly known by a person skilled inthe art. In case of conflict, the definitions provided herein willprevail. Unless specified otherwise, all the percentages, portions andratios in the present invention are on weight basis.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the present specification and associated claims areto be understood as being modified in all instances by the term “about.”The terms “about” and “approximate,” when used along with a numericalvariable, generally means the value of the variable and all the valuesof the variable within a measurement or an experimental error (e.g., 95%confidence interval for the mean) or within a specified value (e.g.,±20%, ±10%, ±5%) within a broader range. For instance, the term “about”typically means having a value falling within an accepted standard oferror of the mean when considered by one of ordinary skill in the art.Preferably, the term “about” refers to ±20%, preferably ±10%, and morepreferably ±5% of the value or range to which it refers.

Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the embodiments of the present invention.Whenever a numerical range with a lower limit and an upper limit isdisclosed, any number and any included range falling within the range isspecifically disclosed. In particular, every range of values (of theform, “from about a to about b,” or, equivalently, “from approximately ato b,” or, equivalently, “from approximately a-b”) disclosed herein isto be understood to set forth every number and range encompassed withinthe broader range of values. Also, the terms in the claims have theirplain, ordinary meaning unless otherwise explicitly and clearly definedby the patentee. Moreover, the indefinite articles “a” or “an,” as usedin the claims, are defined herein to mean one or more than one of theelements that it introduces.

While compositions and methods are described herein in terms of“comprising” various components or steps, the compositions and methodscan also “consist essentially of” or “consist of” the various componentsand steps.

As used herein the term “mifepristone” refers to mifepristone free baseor its pharmaceutically acceptable salts, solvates or hydrates thereof.In principle, any crystalline form or amorphous form of mifepristone maybe used for manufacturing the inventive pharmaceutical compositions ofthe present invention.

The term “pharmaceutically acceptable” substances mean those, which,according to a common medical judgment, are suitable to be in contactwith a tissue of a patient without any inappropriate toxicity,irritation, allergic response, etc., have a reasonable balance betweenadvantages and disadvantages, and can be applied to its target useeffectively.

The term “pharmaceutically acceptable salt” refers to mifepristone saltswhich are formed with inorganic or organic acids.

As used in the description herein and throughout the claims that follow,the meaning of “a,” “an,” and “the” includes plural reference unless thecontext clearly dictates otherwise. Also, as used in the descriptionherein, the meaning of “in” includes “in” and “on” unless the contextclearly dictates otherwise.

The term “particles” refers to individual drug substance particleswhether the particles exist singly or are agglomerated. Thus, acomposition comprising particulate mifepristone may contain agglomeratesthat are well beyond the size limit of about 1 pm specified herein.However, if the mean size of the primary drug substance particles (i.e.,mifepristone) comprising the agglomerate are less than about 1 pmindividually, then the agglomerate itself is considered to satisfy theparticle size constraints defined herein and the composition is withinthe scope of the invention.

The terms “nano-particle(s)” and “nano-sized” refers to mifepristoneparticles produced by the methods of this invention that in general havean average (arithmetic mean) diameter of <1 pm, particularly betweenabout 1-1000 nm, about 10-800 nm, about 50-700 nm, about 100-700 nm. Theaverage diameter of a nano-particle may be determined as the “averageeffective particle diameter”, which may be measured by e.g., dynamiclight scattering methods, or microscopy.

The term “particle-size distribution” (PSD), as used herein, refers tothe relative amounts of particles present, sorted according to size.

The terms “pharmaceutical composition,” “pharmaceutical product,”“pharmaceutical dosage form,” “dosage form,” “composition”,“formulation”, etc., refer to a pharmaceutical composition administeredto a patient in need of, treatment, including but not limited to tablet,hard-gelatin capsule, soft-gelatin capsule, oral suspension, oralsolution, enteric coated hard-gelatin capsule, enteric coatedsoft-gelatin capsule, to cores, coated cores, pellets, micro pellets,pills, compressed tablets, granules, spheres, capsules and the like.

By “effective amount” or “therapeutically effective amount” is meant theamount of a drug sufficient to treat, prevent, or ameliorate a conditionin a subject or patient. The effective amount of mifepristone orpharmaceutically acceptable salt thereof, used to practice the presentinvention for therapeutic management of a condition may be determinedand adjusted by a person of ordinary skill to provide the appropriateamount and dosage regimen, e.g., depending upon one or more of themanner of administration, the age, body weight, sex, and/or generalhealth of the patient.

The term “solubility” means solubility of mifepristone or itspharmaceutically acceptable salts in media such as water, buffer,gastrointestinal simulated fluid, gastrointestinal fluid and the like.

The term “in vivo” in general means in the living body of a plant oranimal, whereas the term “in vitro” generally means outside the body andin an artificial environment.

The term “reduced dose” as used herein refers to a therapeuticallyeffective dose of mifepristone, which is less than the usual orconventional dose required to produce equal or higher therapeuticeffect.

The term “subject” refers to an animal, including a human or non-human.The terms patient and subject may be used interchangeably herein.

The term “bioavailability” indicates the extent to which a drug oranother substance is utilized by a target tissue after administration.For example, “bioavailability” may refer to the fraction of drugabsorbed following administration to a subject or patient under fed orfasted state.

The term “bioequivalence” refers to the absence of a significantdifference between the bioavailability, e.g., the mean ratio of AUC(over 24 hours) and the mean ratio of C_(max) is within 80% to 125%between two pharmaceutical drug products (e.g., a test composition and areference composition) over the course of a period of time, at the samedose and under the same conditions. The determination of whether or nota test composition is bioequivalent to a reference composition isdetermined by performing a study, referred to as a bioequivalence orcomparative bioavailability study, in a group of subjects undercontrolled conditions.

The term “peak time of plasma drug concentration (T_(max))” means thetime when peak plasma drug concentration (C_(max)) is attained afterdrug administration.

The term “peak plasma drug concentration (C_(max))” means the maximumplasma drug concentration attained after drug administration.

The term “AUC_(0-infinity)” means the area under a plasma drugconcentration—time curve from time point of 0 to infinity after drugadministration.

The term “AUC_(0-t)” means the area under a plasma drugconcentration—time curve from time point of 0 to t after drugadministration, “t” is time in hours may range from 24-72 hour.

As used herein, the term “enhanced bioavailability” refers to increasein concentration of the active ingredient in the body fluid provided bythe compositions of the present invention when compared to concentrationof the active ingredient in the body fluid obtained from KORLYM® underidentical conditions. In certain aspects, the bioavailability (e.g.,AUC, C_(max) and/or T_(max)) of mifepristone when formulated asdescribed herein is enhanced at least about 15%, but may be greater than20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%,350%, 375% or 400% of the dose administered when compared to KORLYM®under identical conditions.

Pharmacokinetic parameters for the inventive pharmaceutical compositionscan be measured in a single or multiple dose study using a replicate ora non-replicate design. For example, but not limited to, thepharmacokinetic parameters can be measured in a single dosepharmacokinetic study using a two-period, two-sequence crossover design.Alternately, a four-period, replicate design crossover study may also beused. Pharmacokinetic parameters characterizing rate and extent ofmifepristone absorption are evaluated statistically. The area under theplasma concentration-time curve from time zero to the time ofmeasurement of the last quantifiable concentration (AUC_(0-t)) and toinfinity (AUC_(0-infinity)), C_(max), and T_(max) can be determinedaccording to standard techniques. Statistical analysis ofpharmacokinetic data is performed on logarithmic transformed data (e.g.,AUC_(0-t), AUC_(0-infinity), or C_(max) data) using analysis of variance(ANOVA).

Reference throughout this specification will be made to theadministration of a pharmaceutical composition under fed conditions orfasted conditions. It is well understood in the art that thepharmacokinetic performance of some compositions is affected by thepresence or absence of food in the gastro-intestinal system. Thesereferences thus relate to the normally accepted administrationcircumstances that are referred to in the art as “fed” or “fasted.”

The term “food effect” as used herein means food-drug interactions whicheither decrease or increase the extent of drug absorption. In otherwords, the bioavailability for a drug is altered when administered underfasted state, in comparison to the drug when administered in the fedstate. It may refer to a relative difference in one or more ofAUC_(0-infinity), AUC_(0-t) and/or C_(max) of a drug, when said drug ora formulation thereof is administered orally to a human, concomitantlywith food or in a fed state as compared to the same values when the sameformulation is administered in a fasted state or without food.

In certain aspects, the food effect may be defined as the ratio of theC_(max) and/or AUC values of the tested drug in fed versus fastedstates. Measuring the C_(max) and/or AUC values of the tested drug infed and in fasted states is standard practice in the art. Reduction offood effect can be determined by comparing the value of the ratio fromthe composition or pharmaceutical composition of the invention and thevalue of a composition without the solubilized form disclosed in thepresent invention.

In certain aspects, the pharmaceutical compositions described hereinreduce or eliminate the food effect. As used herein, “reducing the foodeffect” refers to narrowing the difference in bioavailability, e.g.,AUC_(0-infinity), AUC_(0-t) and/or C_(max) for a drug administered underfasted states in comparison to the drug administered under fed states.In certain aspects, the food effect is eliminated. Thus, upon oraladministration of a pharmaceutical composition as described herein, to amammal in need thereof, there is not a significant food effect. In otherwords, the difference between a pharmacokinetic parameter measured afteroral administration to a mammal with and without food, respectively, isless than 40%, e.g., less than 35%, less than 30%, less than 25%, lessthan 20%, less than 15%, less than 10 or less than 5%. Preferably thecomposition or the pharmaceutical composition of the invention has atleast 15% reduced food effect, preferably 20%, preferably 25%,preferably 30%, preferably 40%, reduced food effect.

In an embodiment, the inventive pharmaceutical composition as describedherein, wherein said composition upon oral administration in fed stateexhibits bioequivalence to a commercially available reference drugproduct corresponding to National Drug Code Number 76346-073 and NDA202107 (KORLYM®), in the fed state, and wherein said bioequivalence isestablished by at least one of: (i) a confidence interval for meanAUC_(0-t) between about 80% and about 125%; (ii) a confidence intervalfor mean AUC_(0-infinity) between about 80% and about 125%; (iii) aconfidence interval for mean C_(max) between about 80% and about 125% orcombinations thereof.

In an embodiment, the inventive pharmaceutical composition comprising:(a) 240 mg mifepristone; and (b) one or more pharmaceutically acceptableexcipients; wherein said composition upon oral administration, in fedstate, exhibits bioequivalence to reference drug product correspondingto National Drug Code Number 76346-073 and NDA 202107 (KORLYM®), in thefed state, and wherein said bioequivalence is established by at leastone of: (i) a confidence interval for least square geometric mean ofAUC_(0-t) between about 80% and about 125%; (ii) a confidence intervalfor least square geometric mean of AUC_(0-infinity) between about 80%and about 125%; (iii) a confidence interval for least square geometricmean of C_(max) between about 80% and about 125% or combinationsthereof.

The difference in AUC of the compositions of the present invention, whenadministered in the fed versus the fasted state, preferably is less thanabout 100%, less than about 90%, less than about 80%, less than about70%, less than about 65%, less than about 60%, less than about 55%, lessthan about 50%, less than about 45%, less than about 40%, less thanabout 35%, less than about 30%, less than about 25%, less than about20%, less than about 15%, less than about 10%, less than about 5%, orless than about 3%.

The difference in C_(max) of the compositions of the present invention,when administered in fed versus the fasted state, preferably is lessthan about 100%, less than about 90%, less than about 80%, less thanabout 70%, less than about 65%, less than about 60%, less than about55%, less than about 50%, less than about 45%, less than about 40%, lessthan about 35%, less than about 30%, less than about 25%, less thanabout 20%, less than about 15%, less than about 10%, less than about 5%,or less than about 3%.

In some aspects, administration of the pharmaceutical composition to fedand fasted subjects produce a coefficient of variation in AUC_(0-t),C_(max) and/or AUC_(0-infinity) of less than about 60% (e.g., less than55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, and 15%). In particularembodiments, the coefficient of variation in AUC_(0-t), C_(max) and/orAUC_(0-infinity) is of from about 20% to about 60% (e.g., from 20% to30%, from 20% to 35%, from 20% to 40%, from 20% to 45%, from 20% to 50%,from 20% to 55%, from 30% to 35%, from 30% to 40%, from 30% to 45%, from30% to 50%, from 30% to 55%, from 30% to 60%, from 35% to 40%, from 35%to 45%, from 35% to 50%, from 35% to 55%, from 35% to 60%, from 40% to45%, from 40% to 50%, from 40% to 55%, from 40% to 60%, from 45% to 50%,from 45% to 55%, from 45% to 60%, from 50% to 55%, from 50% to 60%, andfrom 55% to 60%).

The difference in AUC_(0-t) of the compositions of the presentinvention, when administered in fasting versus fed state, preferably isless than about 100%, less than about 90%, less than about 80%, lessthan about 70%, less than about 65%, less than about 60%, less thanabout 55%, less than about 50%, less than about 45%, less than about40%, less than about 35%, less than about 30%, less than about 25%, lessthan about 20%, less than about 15%, less than about 10%, less thanabout 5%, or less than about 3%.

The difference in AUC_(0-t) of the compositions of the presentinvention, when administered in fed versus fed state, preferably is lessthan about 100%, less than about 90%, less than about 80%, less thanabout 70%, less than about 65%, less than about 60%, less than about55%, less than about 50%, less than about 45%, less than about 40%, lessthan about 35%, less than about 30%, less than about 25%, less thanabout 20%, less than about 15%, less than about 10%, less than about 5%,or less than about 3%.

The difference in C_(max) of the compositions of the present invention,when administered in fasting versus the fed state, preferably is lessthan about 100%, less than about 90%, less than about 80%, less thanabout 70%, less than about 65%, less than about 60%, less than about55%, less than about 50%, less than about 45%, less than about 40%, lessthan about 35%, less than about 30%, less than about 25%, less thanabout 20%, less than about 15%, less than about 10%, less than about 5%,or less than about 3%.

The difference in C_(max) of the compositions of the present invention,when administered in fed versus the fed state, preferably is less thanabout 100%, less than about 90%, less than about 80%, less than about70%, less than about 65%, less than about 60%, less than about 55%, lessthan about 50%, less than about 45%, less than about 40%, less thanabout 35%, less than about 30%, less than about 25%, less than about20%, less than about 15%, less than about 10%, less than about 5%, orless than about 3%.

In some aspects, administration of the pharmaceutical composition tofasting and fed subjects produce a coefficient of variation inAUC_(0-t), C_(max) and/or AUC_(0-infinity) of less than about 60% (e.g.,less than 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, and 15%). Inparticular embodiments, the coefficient of variation in C_(max) and/orAUCO-t is of from about 20% to about 60% (e.g., from 20% to 30%, from20% to 35%, from 20% to 40%, from 20% to 45%, from 20% to 50%, from 20%to 55%, from 30% to 35%, from 30% to 40%, from 30% to 45%, from 30% to50%, from 30% to 55%, from 30% to 60%, from 35% to 40%, from 35% to 45%,from 35% to 50%, from 35% to 55%, from 35% to 60%, from 40% to 45%, from40% to 50%, from 40% to 55%, from 40% to 60%, from 45% to 50%, from 45%to 55%, from 45% to 60%, from 50% to 55%, from 50% to 60%, and from 55%to 60%).

The nano-particles of a solid material, and in particular nano-particlesof a poorly soluble or essentially insoluble solid material, findsbeneficial use in numerous applications related to the increase insurface area achieved as a result of size reduction. When incorporatedinto a mixture, formula, composition, dispersion, coating, powder,lyophilizate, suspension, matrix, and the like, a solid material in theform of smaller particles exhibit greater homogeneity in macroscopic andimproved microscopic or kinetic properties such as increased rate ofdissolution into a volume of solvent or a volume of liquid including apseudo-infinite solvent pool volume.

The nano-particles of a solid material often requires presence of one ormore surface-active substance particularly on the surface of theparticles to achieve or augment particle stability.

In certain embodiments, following oral administration of the inventivepharmaceutical compositions enhances the bioavailability of themifepristone relative to the reference composition, making it possibleto use reduced doses of mifepristone (e.g., 100, 110, 120, 130, 140,150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260 and 270 mg)while achieving same or substantially similar therapeutic efficacy ascompared to the commercially approved dose (300 mg). On the other hand,the inventive pharmaceutical composition allows administration of alower dose while retaining the therapeutic efficacy of mifepristone(e.g., 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220,230, 240, 250, 260 and 270 mg), resulting in reduced undesirable sideeffects such as nausea, fatigue, headache, decreased blood potassium,arthralgia, vomiting, peripheral edema, hypertension, dizziness,decreased appetite, endometrial hypertrophy, associated with the use ofconventional dose.

In certain embodiments, following oral administration of the inventivepharmaceutical compositions enhances the bioavailability of themifepristone making it possible to use reduced doses of mifepristone(e.g., 480 mg) while achieving same or substantially similar therapeuticefficacy as compared to the commercially approved dose of KORLYM® (i.e.,600 mg). On the other hand, the inventive pharmaceutical compositionallows administration of a lower dose while retaining the therapeuticefficacy of mifepristone (e.g., 480 mg), resulting in reducedundesirable side effects such as nausea, fatigue, headache, decreasedblood potassium, arthralgia, vomiting, peripheral edema, hypertension,dizziness, decreased appetite, endometrial hypertrophy, associated withthe use of conventional dose of KORLYM® (i.e., 600 mg).

In certain embodiments, following oral administration of the inventivepharmaceutical compositions enhances the bioavailability of themifepristone making it possible to use reduced doses of mifepristone(e.g., 720 mg) while achieving same or substantially similar therapeuticefficacy as compared to the commercially approved dose of KORLYM® (i.e.,900 mg). On the other hand, the inventive pharmaceutical compositionallows administration of a lower dose while retaining the therapeuticefficacy of mifepristone (e.g., 720 mg), resulting in reducedundesirable side effects such as nausea, fatigue, headache, decreasedblood potassium, arthralgia, vomiting, peripheral edema, hypertension,dizziness, decreased appetite, endometrial hypertrophy, associated withthe use of conventional dose of KORLYM® (i.e., 900 mg).

In certain embodiments, following oral administration of the inventivepharmaceutical compositions enhances the bioavailability of themifepristone making it possible to use reduced doses of mifepristone(e.g., 960 mg) while achieving same or substantially similar therapeuticefficacy as compared to the commercially approved dose of KORLYM® (i.e.,1200 mg). On the other hand, the inventive pharmaceutical compositionallows administration of a lower dose while retaining the therapeuticefficacy of mifepristone (e.g., 960 mg), resulting in reducedundesirable side effects such as nausea, fatigue, headache, decreasedblood potassium, arthralgia, vomiting, peripheral edema, hypertension,dizziness, decreased appetite, endometrial hypertrophy, associated withthe use of conventional dose of KORLYM® (i.e., 1200 mg).

In certain embodiments, following oral administration of the inventivepharmaceutical composition to subjects (e.g., in fed or fastedcondition), the mean bioavailability is greater than about 20% (e.g.,greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, or even 99%) or between about 20% to about 90% (e.g.,from 20% to 30%, from 20% to 40%, from 20% to 50%, from 20% to 60%, from20% to 70%, from 20% to 80%, from 20% to 90%, from 30% to 40%, from 30%to 50%, from 30% to 60%, from 30% to 70%, from 30% to 80%, from 30% to90%, from 40% to 50%, from 40% to 60%, from 40% to 70%, from 40% to 80%,from 40% to 90%, from 50% to 60%, from 50% to 70%, from 50% to 80%, from50% to 90%, from 60% to 70%, from 60% to 80%, from 60% to 90%, from 70%to 80%, from 70% to 90%, and from 80% to 90%).

In an embodiment, composition comprising effective amount ofnano-particles of mifepristone, exhibits a level of total relatedsubstances less than about 5% (w/w), preferably less than about 4%(w/w), preferably less than about 3% (w/w), preferably less than about2% (w/w), preferably less than about 1.5% (w/w), preferably less thanabout 1% (w/w), preferably less than about 0.5 (w/w) as measured byHPLC.

In an embodiment, composition comprising an effective amount ofnano-particles of mifepristone, exhibits a level of any unknown impurityless than about 1 (w/w), preferably less than about 0.5% (w/w),preferably less than about 0.4% (w/w), preferably less than about 0.3%(w/w), preferably less than about 0.2% (w/w), preferably less than about0.15% (w/w), more preferably less than about 0.1% (w/w) as measured byHPLC.

Certain embodiments herein relate to inventive pharmaceuticalcompositions which are stable, e.g., stable over the shelf life of thedrug product. As used herein, the term “stable” is defined as no morethan about 5% loss of mifepristone under typical commercial storageconditions. In certain embodiments, the compositions of the presentinvention will have no more than about 3% loss of mifepristone, morepreferably, no more than about 2% loss of mifepristone, under typicalcommercial storage conditions. The composition retains at least about95% of the potency of mifepristone after storing the composition at 40°C. and 75% relative humidity for at least three months. In certainaspects, the term “stable” refers to chemical stability, whereinpreferably not more than 2% w/w of total related substances, morepreferably not more than 1.5% w/w of total related substances are formedon storage at accelerated conditions of stability at 40° C. and 75%relative humidity or at 25° C. and 60% relative humidity for a period ofat least three months or to the extent necessary for use of thecomposition. In certain aspects, the term “stable” refers to that themifepristone particles do not appreciably flocculate or agglomerate dueto interparticle attractive forces, or otherwise significantly increasein particle size over time.

An embodiment relates to a pharmaceutical composition comprising aneffective amount of mifepristone, wherein the level of any unknownimpurity is less than about 1% (w/w), preferably less than about 0.8%(w/w), preferably less than about 0.5% (w/w) as measured by HPLC, whenstored at 25° C./60% RH for at least 3 months.

In particular, the N-Desmethyl mifepristone impurity (i.e.,(11β-[4-(Methylamino) phenyl]-17β-hydroxy-17α-(1-propynyl)estra-4,9-dien-3-one) may be monitored. The structure of N-Desmethylmifepristone is shown below:

An embodiment relates to a pharmaceutical composition comprising aneffective amount of mifepristone, wherein the level of N-Desmethylmifepristone impurity is preferably not more than about 1% (w/w), morepreferably not more than about 0.8% (w/w), as measured by HPLC, whenstored at 25° C./60% RH for at least 3 months.

Nano-Suspension of Mifepristone

The term “nano-suspension” refers to colloidal, solid-liquid systemswith a particle size of less than one micrometer. In general,nano-suspensions are stabilized by suspension-aid.

In one embodiment, the invention relates to pharmaceutical compositioncomprising a therapeutically effective amount of mifepristone particlesand one or more pharmaceutical acceptable excipient, wherein themifepristone particles have a D₉₀ equal to or less than about 1000 nm.

Surprisingly and unexpectedly, it has been found that compositions fortablets comprising up to 300 mg, mifepristone particles having a D90(90% of the volume) less than 1000 nm lead to consistent and improvedin-vivo dissolution in humans (at physiologic pH), hence, consistent andimproved exposure to mifepristone and glucocorticoid receptor inhibitionthat will lead to consistency in therapeutic effect with improved safetyprofile. Accordingly, the invention provides a pharmaceuticalcomposition comprising mifepristone particles having a D90 equal to orless than about 1000 nm as measured by a laser light scattering method,and a pharmaceutically acceptable diluent. It is preferred that themifepristone particles in the composition have a D90 not exceeding 1000nm. It is noted the notation DX means that X % of the volume ofparticles have a diameter less than a specified diameter D. Thus a D90of 1000 nm means that 90% of the volume of particles in an mifepristonecomposition have a diameter less than 1000 nm.

The range of particle sizes preferred for use in the invention is D90less than 1000 nm, more preferably D90 less than 900 nm, even morepreferably D90 less than 800 nm, and most preferably D90 less than 700nm. The particle sizes stipulated herein refer to particle sizes weredetermined using a laser light scattering technique.

In one embodiment, the invention relates to a stable nano-suspensioncomprising: (a) nano-sized mifepristone; and (b) one or morepharmaceutically acceptable excipients are selected from suspension-aid,diluents, binders, disintegrants, lubricants, glidants, surfactants,solubilizers, plasticizers, surface stabilizers, antioxidants, coloringagent, coating agent, flavors, preservatives, and combinations thereof.

In one embodiment, the invention relates to a stable nano-suspensioncomprising: (a) nano-sized mifepristone; and (b) at least onesuspension-aid.

In one embodiment, the invention relates to a stable nano-suspensioncomprising: (a) nano-sized mifepristone; (b) at least onesuspension-aid; (c) at least one surfactant, and (d) at least onesurface stabilizer.

In other embodiment, the invention relates to a stable nano-suspensioncomprising: (a) nano-sized mifepristone; and (b) hydroxypropylmethylcellulose; and (c) at least one surfactant.

In other embodiment, the invention relates to a stable nano-suspensioncomprising: (a) nano-sized mifepristone; (b) nano-suspension-aid; and(c) sodium lauryl sulphate and (d) docusate sodium.

In other embodiment, the invention relates to a stable nano-suspensioncomprising: (a) nano-sized mifepristone; (b) hydroxypropylmethylcellulose; and (c) sodium lauryl sulphate and (d) docusate sodium.

In other embodiment, the invention relates to a stable nano-suspensioncomprising: (a) mifepristone having D₉₀ of less than about 1000 nm; (b)at least one suspension-aid; and (c) at least one surfactant.

In other embodiment, the invention further relates to a stablenano-suspension composition comprising: (a) mifepristone having D₅₀ ofless than about 1000 nm; (b) hydroxypropyl methylcellulose; and (c) atleast one surfactant.

In other embodiment, the invention further relates to a stablenano-suspension composition comprising: (a) mifepristone having D₁₀ ofless than about 1000 nm; (b) hydroxypropyl methylcellulose; (c) sodiumlauryl sulphate and (d) docusate sodium.

In other embodiment, the invention relates to a stable nano-suspensioncomposition comprising: (a) nano-sized mifepristone; (b) at least onesuspension-aid; and (c) at least one surfactant, wherein thenano-suspension was prepared by wet-media milling process.

In other embodiment, the invention relates to a stable nano-suspensioncomposition comprising: (a) nano-sized mifepristone having an averageparticle size of less than about 1000 nm; (b) at least onesuspension-aid; and (c) at least one surfactant, wherein thenano-suspension was prepared by wet-milling process.

In a further embodiment, the process for preparing nano-suspension ofmifepristone comprises (a) adding at least one surfactant to thepurified water in a suitable container, (b) adding mifepristone to step(a) and stirred continuously to obtain mifepristone dispersion, (c)homogenizing the above mifepristone dispersion to obtain mifepristoneslurry and (d) nano-sizing mifepristone slurry in a ball-mill chamber toobtain nano-suspension containing desired particle size of mifepristone.

In a further embodiment, the process for preparing nano-suspension ofmifepristone comprises (a) adding at least one suspension-aid to thepurified water in a suitable container, (b) adding mifepristone to step(a) and stirred continuously to obtain mifepristone dispersion, (c)homogenizing the above mifepristone dispersion to obtain mifepristoneslurry and (d) nano-sizing mifepristone slurry in a ball-mill chamber toobtain nano-suspension containing desired particle size of mifepristone.

In a further embodiment, the process for preparing nano-suspension ofmifepristone comprises (a) adding at least one suspension-aid and atleast one surfactant to the purified water in a suitable container, (b)adding mifepristone to step (a) and stirred continuously to obtainmifepristone dispersion, (c) homogenizing the above mifepristonedispersion to obtain mifepristone slurry and (d) nano-sizingmifepristone slurry in a ball-mill chamber to obtain nano-suspensioncontaining desired particle size of mifepristone.

In a further embodiment, the process for preparing nanostructuredmifepristone comprises a) adding at least one surfactant to the purifiedwater in a suitable container, b) adding at least one suspension-aid tostep (a) with continuous stirring, c) optionally, adding at least oneadditional excipient to the step (b); d) adding mifepristone to step (c)with continuous stirring to obtain mifepristone dispersion; e)homogenizing the above mifepristone dispersion to obtain mifepristoneslurry; and f) nano-sizing mifepristone slurry in ball-mill to obtainnano-suspension containing desired particle size of mifepristone.

In another embodiment, the process for preparing nano-suspensionmifepristone comprises a) adding specified amount of docusate sodium tothe purified water in a suitable container, b) adding sodium laurylsulphate (KOLLIPHOR® SLS Fine) to the step (a) and stirred continuouslyto obtain a solution, c) adding HPMC (METHOCEL® E5 LV/METHOCEL® E3 LV)to the step (b) and stirred continuously to obtain a solution, d) addingmifepristone was added to the step (c) and stirred for 5 minutes toobtain mifepristone dispersion, and e) homogenizing the abovemifepristone dispersion using IKA's Ultra TURRAX® homogenizer at about1000 RPM for 15 minutes. The above homogenized mifepristone slurry wasnano-sized in a ball-mill chamber to obtain nano-suspension containingmifepristone of desired particle size.

The homogenizer is a laboratory or industrial equipment used for thehomogenization of various types of materials not limited to drugs.Different models of homogenizers were available based on variousphysical technologies for disruption. The mortar and pestle, is used forthousands of years, is a standard tool even in modern laboratories. Themore modern solutions are based on blender type instruments, bead mills,ultrasonic treatment (also sonication), rotor-stator mechanical, highpressure, and many other physical forces. For example, there aredifferent types of homogenizers are available for the same piece ofmechanical homogenizing equipment, including Cell Lysor, Disperser, HighShear Mixer, Homogenizer, Polytron, Rotor Stator Homogenizer, Sonicatoror Tissue Tearor.

In an embodiment, milling or nano-micronization can also be performed toachieve desired particle sizes or distributions. Equipment that may beused for particle size reduction include, without limitation, ballmills, roller mills, hammer mills, and jet mills. Methods that may beused for particle size reduction include co-precipitation, wetsuspension/dispersion milling, dry powder milling & homogenization.

In an embodiment, the ball mill comprises a vessel or vial filled withballs, or rods, constructed from a variety of materials such as ceramic,agate, silicon nitride, sintered corundum, zirconia, chrome steel, Cr—Nisteel, tungsten carbide or plastic polyamide. The material to be milledis placed inside the vessel, which is made to rotate or vibrate at aparticular speed or frequency. The movement of the vessel causes theballs to cascade or move in a particular pattern, colliding with eachother and with the opposing inner wall of the vessel. Size reduction ofthe drug particles is affected from the impact they receive from theballs as well as attritive forces arising from the movement of the ballsrelative to each other. The quantities of the balls and startingmaterial determine the extent of fill of the vessel and the intensity ofthe milling process. Typically, the vessel is filled by the balls andstarting material to 50% and 25% of the total volume of the vessel,respectively, although variations exist in the literature. In the caseof a rotating vessel, rotation is usually carried out at 50-85% of thecritical speed, defined as the speed at which the balls cease to cascadeowing to the centrifugal force imparted by the rotating vessel. Apartfrom its comminution function, ball milling also serves as an intensivemixing technique capable of producing co-ground drug-excipient mixturescomprising amorphous drug forms intimately mixed with suitablehydrophilic excipients at the molecular level.

In a further embodiment, the present invention relates to a process forpreparing a nano-suspension of mifepristone comprising: (i) providing anadmixture of mifepristone, an aqueous dispersion medium, and millingmedia; and (ii) applying acoustic energy having a frequency of fromabout 10 hertz to 1000 hertz to said admixture, wherein preferably theacoustic energy is a standing wave supplying a linear acceleration offrom about 10 G's to about 100 G's (where “G” is the force of gravity),for a period sufficient to form a nano-suspension having a particle D50of less than about 1 micron.

In another embodiment, the particle size distribution of mifepristonenano-suspension was measured by using Mastersizer 3000 particleanalyzer. The Mastersizer 3000 uses the technique of laser diffractionto measure the particle size and particle size distribution ofmaterials. It does this by measuring the intensity of light scattered asa laser beam passes through a dispersed particulate sample. This data isthen analyzed to calculate the size of the particles that created thescattering pattern.

In some embodiments described herein, the mifepristone of the inventionis distinguished by particle size analysis. In some such embodiments,the mifepristone has a primary particle size of from about 1 nm to about1000 nm, preferably from about 10 nm to about 800 nm, or more preferablyfrom about 100 nm to about 700 nm. In other such embodiments, themifepristone has a primary particle size distribution characterized by:(i) a D10 value of from about 10 nm to about 200 nm; (ii) a D50 value offrom about 50 nm to about 500 nm; or (iii) a D90 value of from about 100nm to about 700 nm; or a combination of (i), (ii) and (iii).

In another embodiment, the D₉₀ particle size of mifepristone can be inthe range of 1 to 1000 nm. Preferably, the D₉₀ particle size ofmifepristone can be between 100 and 700 nm.

In another embodiment, the nano-suspension is separated from the millingmedia, preferably by decanting or by centrifuging over a sieve sizedappropriately to separate the milling media from the nano-suspension.

Suspension-aids adsorb on drug particle surfaces significantly duringmilling and reduce the extent of nano-particle aggregation. Moreover,they reduce the interfacial tension between the hydrophobic drugparticles and water, thereby increasing solubility of poorly solubledrug particles.

According to the embodiments of the invention, the pharmaceuticallyacceptable suspension-aid is selected from one or more of hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), polyvinyl pyrrolidine andvinyl acetate (PVP/VA) copolymer, hydroxypropyl methylcellulosephthalate (HPMCP), hydroxypropyl methylcellulose (HPMC), polyethyleneglycol (PEG), hydroxypropyl cellulose (HPC), carboxymethyl cellulose(CMC), methyl cellulose (MC), hydroxyl ethyl cellulose (HEC) andpolyvinyl pyrrolidine (PVP). The concentration of suspension-aid rangesfrom about 0.5% to about 10% w/w of total composition. The weight ratioof mifepristone to suspension-aid ranges from about 20:1 to about 1:20.

According to the embodiments of the invention, HPMC is availablecommercially, for example, from the Dow Chemical Company under the tradedesignation METHOCEL™, including, for example, METHOCEL™ E3LV, METHOCEL™E5LV, METHOCEL™ E50, and METHOCEL™ K100. METHOCEL™ E5LV is a USP grade,low viscosity HPMC having 28 to 30 (29.1) % methoxyl groups and 7 to 12(9) % hydroxypropyl group substitution. As used herein, hydroxypropylmethylcellulose E5 refers to hydroxypropyl cellulose have a viscosity ofabout 5 (4 to 6) mPas (cps), and hydroxypropyl methylcellulose E50refers to hydroxypropyl cellulose have a viscosity of about 50 (40 to60) mPas (cps). The viscosity for the hydroxypropyl cellulose ismeasured in a 2 weight % solution in water at 20° C. with a Ubbelohdetube viscometer.

In some embodiments, the suspension-aid is combined with a surfactant tohelp maintain dispersion. As is known, the nature and amount ofsurfactant employed will depend upon the suspension-aid employed and thenature of the surface of the particles of the active ingredient.Preferable surfactant suitable for use in nano-suspensions of thepresent invention include, but not limited to, sodium lauryl sulfate(SLS).

The pharmaceutical compositions of the present invention optionally mayinclude one or more other surfactants. The other surfactants can beselected from hydrophilic surfactants or lipophilic surfactants ormixtures thereof. The surfactants can be anionic, nonionic, cationic,and zwitterionic surfactants. Surfactants according to the presentinvention include, but not limited to, polyoxyethylene alkylaryl etherssuch as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether,polyoxyethylene stearyl ether; polyethylene glycol fatty acid esterssuch as PEG monolaurate, PEG dilaurate, PEG distearate, PEG dioleate;polyoxyethylene sorbitan fatty acid ester such as sorbitan fatty acidmono esters such as sorbitan monolaurate, sorbitan monooleate, sorbitansesquioleate, sorbitan trioleate, sodium lauryl sulfate, lecithin,stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylenericin oil, polyoxyethylene fatty acid glycerides, Kolliphor® RH 40,polyethylene glycol 400 distearate, polyethylene glycol—20 dioleate,polyethylene glycol 4-150 mono dilaurate, and polyethylene glycol—20glyceryl stearate; alcohol—oil transesterification products, forexample, polyethylene glycol—6 corn oil; polyglycerized fatty acids, forexample, polyglyceryl—6 pentaoleate; propylene glycol fatty acid esters,for example, propylene glycol monocaprylate; mono and diglycerides, forexample, glyceryl ricinoleate; sterol and sterol derivatives; sorbitanfatty acid esters and its derivatives, for example, polyethyleneglycol—20 sorbitan monooleate and sorbitan monolaurate; polyethyleneglycol alkyl ether or phenols, for example, polyethylene glycol—20 cetylether and polyethylene glycol—10-100 nonyl phenol; sugar esters, forexample, sucrose monopalmitate; ionic surfactants, for example, sodiumcaproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate,propylene glycol alginate, octyl sulfosuccinate disodium, and palmitoylcarnitine; and the like and mixtures thereof. The concentration ofsurfactant ranges from about 0.05% to about 10% w/w of totalcomposition. The weight ratio of mifepristone to surfactant ranges fromabout 50:1 to about 1:50.

Nanonization (the process of making the particles nano-sized) may beperformed in the presence of a surfactant. The absorption of nano-sizedparticles of mifepristone into the bloodstream of a mammal may besignificantly improved when the mifepristone is administered to themammal as a formulation with a surfactant.

The present disclosure is directed to pharmaceutical compositionscomprising nano-sized mifepristone. The compositions comprise nano-sizedmifepristone and at least one surface stabilizer that is preferablyadsorbed on or associated with the surface of the drug. The nano-sizedmifepristone particles have an effective average particle size of lessthan about 1 micron.

The choice of a surface stabilizer for a mifepristone is non-trivial andrequired extensive experimentation to realize a desirable formulation.Accordingly, the present invention is directed to the surprisingdiscovery that nano-sized mifepristone, compositions can be made.

Combinations of more than one surface stabilizer can be used in theinvention. Useful surface stabilizers which can be employed in theinvention include, but are not limited to, known organic and inorganicpharmaceutical excipients. Such excipients include various polymers, lowmolecular weight oligomers, natural products, and surfactants. Surfacestabilizers include nonionic, anionic, cationic, ionic, and zwitterionicsurfactants. The concentration of surface stabilizers range from about0.05% to about 1 w/w of total composition. The weight ratio ofmifepristone to suspension-aid ranges from about 20:1 to about 1:20,preferably from about 10:1 to about 1:10, more preferably from about 2:1to about 1:2.

Representative examples of surface stabilizers useful in the inventioninclude, but are not limited to, hydroxypropylcellulose,polyvinylpyrrolidone, dioctyl sulfosuccinate (docusate sodium), gelatin,casein, lecithin (phosphatides), dextran, gum acacia, cholesterol,tragacanth, stearic acid, benzalkonium chloride, calcium stearate,glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifyingwax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogolethers such as cetomacrogol 1000), polyoxyethylene castor oilderivatives, polyethylene glycols (e.g., Carbowaxs 3550® and 934® (UnionCarbide)), polyoxyethylene stearates, colloidal silicon dioxide,phosphates, carboxymethylcellulose calcium, carboxymethylcellulosesodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate,noncrystalline cellulose, magnesium aluminium silicate, triethanolamine,polyvinyl alcohol (PVA), 4-(1,1,3,3-tetramethylbutyl)-phenol polymerwith ethylene oxide and formaldehyde (also known as tyloxapol,superione, and triton), Tetronic 1508® (T-1508) (BASF WyandotteCorporation), Tritons X-200®, which is an alkyl aryl polyether sulfonate(Rohm and Haas); Crodestas F-110®, which is a mixture of sucrosestearate and sucrose distearate (Croda Inc.);p-isononylphenoxypoly-(glycidol), also known as Olin-1OG® or Surfactant10-G® (Olin Chemicals, Stamford, Conn.); Crodestas SL40® (Croda, Inc.);and SA9OHCO, which is C18H37CH2(CON(CH3)-CH2(CHOH)4(CH2OH)2 (EastmanKodak Co.); decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside;n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecylβ-D-maltoside; heptanoyl-N-methylglucamide;n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexylβ-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noylβ-D-glucopyranoside; octanoyl-N-methylglucamide;n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside;PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative,PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinylpyrrolidone and vinyl acetate, and the like.

In further embodiment, the nano-suspension of mifepristone can beblended or sprayed over one or more intra-granular excipients, asdescribed herein, and then granulated and/or compacted withextra-granular excipients to produce a final blend for encapsulating ortableting.

The inventors of the present application have surprisingly found that acomposition comprising nano-sized mifepristone, comprising at least onesuspension-aid and at least one surfactant, can increase the solubilityof mifepristone in gastrointestinal tract, and can ameliorate theproblem of precipitation or crystallization, thereby increasing theabsorption of mifepristone in vivo and enhance the bioavailabilitythereof.

In an aspect, the inventive composition can alter the absorptionbehavior of mifepristone in vivo, increasing C_(max) and AUC in fastingand fed states.

Pharmaceutical Compositions Comprising Nano-Suspensions of Mifepristone

The nano-suspension may be used for preparing one of the unit dosages

forms described herein (e.g., capsule or tablet). The nano-suspensioncan optionally be further processed before filling or tableting.Exemplary further processing includes spheronizing, pelletizing,milling, injection molding, sieving, and/or calendaring.

Nano-suspension produced by wet media milling are typically stabilizedagainst particle agglomeration using either steric (by means of polymersor nonionic surfactants) or electrostatic (by means of ionicsurfactants) stabilization mechanisms, or sometimes a combination ofboth mechanisms which is referred to as electro-steric stabilization.Although there is one instance of a nano-suspension product beingmarketed in the liquid form (MEGACE® ES), conversion of anano-suspension into a dried powder form that can be further filled intocapsules or compressed into tablets is often desirable to ensure themaximum patient compliance. The drying step can be further necessitatedby the fact that there could be possible stability issues, both physical(such as Ostwald ripening and agglomeration) and chemical (such ashydrolysis) associated with nano-particles in their suspended form.Additionally, for nano-particles, there could also be a risk ofcrystallization upon storage if partial surface amorphization occursduring the wet milling process.

In an embodiment nano-suspension can be best transformed to oralproducts by various methods of solidification but not limited tolyophilization, spray drying, pelletization, electro-spraying andsprayed onto granular material. Stability profile of nano-suspensionalways remains a constraint due to thermodynamically active andelectrostatically charged state of nano-suspension, making them moreprone to Ostwald ripening and agglomeration. To minimize the aggregationproblem and improve the stability, nano-suspensions may be dried to formnanocrystals, which still possess the unique properties of thenano-suspensions. Solidification techniques are best suited for thepurpose of stabilization, as well as easy conversion of nano-suspensionto solid form, without compromising the solubility advantages offered bytechnique.

Freeze-drying and spray drying are one of the most common processes usedto convert a nano-suspension into a solid form. Both these processingmethods result in powders that require further processing to improve thebulk density and flow properties prior to conversion into a tablet or acapsule dosage form. Granulation based approaches, which typicallyresult in densification with improved flow properties of the powder,have also been used.

In an embodiment, the nano-suspension of mifepristone may be combinedwith pharmaceutically acceptable excipients to manufacture inventivepharmaceutical compositions. The one or more pharmaceutically acceptableexcipients are selected from suspension-aid, diluents, binders,disintegrants, lubricants, glidants, surfactants, solubilizers,plasticizers, surface stabilizers, antioxidants, coloring agent, coatingagent, flavors, preservatives, and combinations thereof.

In an embodiment, inventive pharmaceutical compositions comprisingnano-sized mifepristone and pharmaceutically acceptable excipients areprepared by using, but not limited, to wet granulation, dry granulation,and direct compression.

The pharmaceutical compositions comprising nano-sized mifepristone andpharmaceutically acceptable excipients are prepared by wet granulation,which process comprises spraying nano-suspension of mifepristone overintra-granular material. The sprayed granules were dried and sieved. Thesprayed and sieved intra-granular material is mixed with extra-granularmaterial and compressed using tablet compression machine. The tabletswere coated with suitable coating materials.

The process for preparation of inventive pharmaceutical compositioncomprises, spraying nano-sized mifepristone suspension on warmedintra-granular material (silicified microcrystalline cellulose and/orsodium starch glycolate). The sprayed granules are dried at atemperature of 50° C. to 65° C. and sieved through 30 number meshsieves. The sieved intra-granular material is mixed with extra-granularexcipients like sodium starch glycolate (PRIMOJEL®), microcrystallinecellulose (CEOLUS® KG-802), and magnesium stearate (LIGAMED® MF-2-V) andcompressed using tablet compression machine. The tablets were coatedwith suitable coating materials.

The pharmaceutical compositions comprising nano-sized mifepristone andpharmaceutically acceptable excipients are prepared by wet granulationor dry granulation, which process comprises mixing nano-suspension ofmifepristone with intra-granular excipients. The mixed granules weredried and sieved. The dried intra-granular granules were mixed withextra-granular excipients and compressed using tablet compressionmachine. The tablets were coated with suitable coating materials.

In an embodiment, pharmaceutical compositions comprising nano-sizedmifepristone and pharmaceutically acceptable excipients are preparedusing direct compression, which process comprises mixing nano-suspensionof mifepristone and pharmaceutically acceptable excipients, and theresultant mixture is either compressed to tablet or filled in hardgelatin capsules.

The pharmaceutical composition of the present invention is preferably agranulate/particulate material. The granules/particles may be filledinto a capsule or compressed into a tablet. The tablet may optionally becoated with an additional enteric polymer or an immediate-release filmcoating.

The granules of the present invention may be formulated into anysuitable dosage form, including but not limited to oral suspensions,gels, tablets, capsules, immediate release formulations, delayed releaseformulations, controlled release formulations, extended-releaseformulations, pulsatile release formulations, and mixed immediate andcontrolled release formulations.

Other pharmaceutically acceptable excipients may include, but are notlimited to, diluents, binders, disintegrating agents, surfactants,surface stabilizers, plasticizers, lubricants, glidants, chelatingagents, coating agents and the like or mixtures thereof asextra-granular agents.

Suitable diluents include microcrystalline cellulose, silicifiedmicrocrystalline cellulose, calcium carbonate, calciumphosphate-dibasic, calcium phosphate-tribasic, calcium sulfate,cellulose powdered, dextrates, dextrins, dextrose excipients, fructose,kaolin, lactitol, lactose, mannitol, sorbitol, starch, starchpregelatinized, sucrose, sugar compressible, sugar confectioners and thelike.

In an embodiment, diluent is included either in nano-suspension orintra-granular material or extra-granular material or both. The diluentconcentration ranges from about 10% to about 60% w/w of totalcomposition. The diluent concentration in the intra-granular materialranges from about 10% to about 60% w/w of total composition, preferablyabout 25% to about 35%.

Suitable binders include methyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, polyvinyl pyrrolidone, microcrystallinecellulose, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol,pullulan, pregelatinized starch, agar, tragacanth, sodium alginate,propylene glycol and the like. The concentration of binder ranges fromabout 1% to about 20% w/w of total composition, preferably about 10% toabout 15% w/w.

Suitable disintegrating agents include croscarmellose sodium, lowsubstituted hydroxypropyl cellulose (L-HPC), sodium starch glycollate,carboxymethyl cellulose, calcium carboxymethyl cellulose, sodiumcarboxymethyl cellulose, starch, crystalline cellulose, hydroxypropylstarch, pregelatinized starch, and the like and mixtures thereof. Theconcentration of disintegrating agent ranges from about 1% to about 10%w/w of total composition.

Suitable lubricants or glidants include colloidal silicon dioxide(AEROSIL®), stearic acid, magnesium stearate, calcium stearate, talc,hydrogenated castor oil, sucrose esters of fatty acid, microcrystallinewax, yellow beeswax, white beeswax, and the like and mixtures thereof.The concentration of lubricant or glidant ranges from about 0.5% toabout 5% w/w of total composition.

Suitable colouring agent include dyes and pigments such as iron oxidered or yellow, titanium dioxide, talc. The concentration of colouringagent ranges from about 0.1% to about 1% w/w of total composition.

Suitable chelating agents include, one or more of, but not limited toethylenediaminetetraacetic acid (EDTA), disodium EDTA and derivativesthereof, citric acid and derivatives thereof, niacinamide andderivatives thereof, and sodium desoxycholate and the like or mixturesthereof. The concentration of chelating agent ranges from about 0.1% toabout 1% w/w of total composition.

Suitable antioxidants include, one or more of, but not limited toa-tocopherol, butylated hydroxytoluene (BHT), butylated hydroxyanisole(BHA), tert-butylhydroquinone (TBHQ), propyl gallate (PG) and the likeor mixtures thereof. The concentration of antioxidant ranges from about0.1% to about 1% w/w of total composition.

The pharmaceutical composition may also optionally be coated, i.e., sealcoated and/or enteric coated and/or film coated. Preferably, thepharmaceutical composition may be seal coated and finally film coated orit may be seal coated and further enteric coated. Optionally,pharmaceutical compositions of the invention may be film coated.Preferably, the film coating polymer may be present in an amount fromabout 1 to 10% w/w.

The in vitro dissolution rate may be determined using an USP ApparatusII at 75 RPM (Rotation Per Minute), in 0.01N HCL 900 mL dissolutionmedia at 37° C. In certain aspects, the in vitro release rate is chosensuch that the in vivo peak plasma levels of mifepristone occur betweenabout 5 minutes to about 6 hours after administration of the compositionto a patient. In certain embodiments, not less than 50% of mifepristoneis released after about 30 minutes. In other aspects, the in vitrodissolution rate is not less than about 50% in 60 minutes.

In certain embodiments, the inventive pharmaceutical compositionssuitable for oral administration comprising nano-sized mifepristone,wherein at least 50% of the mifepristone is released after about 30minutes as determined using USP Apparatus II at 75 RPM in 0.01N HCL 900mL dissolution media at 37° C.

In certain embodiments, the inventive pharmaceutical compositionssuitable for oral administration comprising nano-sized mifepristone,wherein at least 50% of the mifepristone is released after about 60minutes as determined using USP Apparatus II at 75 RPM in 0.01N HCL 900mL dissolution media at 37° C.

The in vitro dissolution rate may be determined using an USP ApparatusII at 50 RPM (Rotation Per Minute), in pH 1.8 KCl buffer 900 mLdissolution media at 37° C. In certain aspects, the in vitro releaserate is chosen such that the in vivo peak plasma levels of mifepristoneoccur between about 5 minutes to about 6 hours after administration ofthe composition to a patient. In certain embodiments, not less than 50%of mifepristone is released after about 30 minutes. In other aspects,the in vitro dissolution rate is not less than about 50% in 60 minutes.In certain embodiments, not less than 70% of mifepristone is releasedwithin 45 minutes of dissolution.

In one embodiment, the invention relates to a pharmaceutical compositioncomprising a therapeutically effective amount of mifepristone particles,wherein the mifepristone particles have a D₉₀ equal to or less thanabout 1000 nm, and wherein, as measured using a USP Apparatus 2 at apaddle rotation speed of 50 RPM in 900 mL, of dissolution medium at 37°C., at least 70 wt % of mifepristone in the pharmaceutical compositiondissolves within 45 minutes in the dissolution medium, and thedissolution medium is pH 1.8 potassium chloride buffer.

In one embodiment, the invention relates to a pharmaceutical compositioncomprising: (a) mifepristone; and (b) one or more pharmaceuticallyacceptable excipients; wherein the composition provides an in-vitromifepristone release of not less than about 70 wt % of mifepristone,within 45 minutes of dissolution in a 900 mL pH 1.8 potassium chloridedissolution medium, measured using USP Apparatus II, at 50 RPM and 37°C.

Methods of Treatment

The compositions of the present invention may be used for the sameindications as KORLYM®, including to treat high blood sugar(hyperglycemia) caused by high cortisol levels in the blood(hypercortisolism) in adults with endogenous Cushing's syndrome who havetype 2 diabetes mellitus or glucose intolerance and have failed surgeryor cannot have surgery.

The present invention provides methods of therapeutically treatingCushing's syndrome by administering a quantity of: a composition of theinvention; or dosage form comprising a composition of the invention,administered dose ranges from about 100 mg to about 1200 mg ofmifepristone per day, either in a single or divided dose. In someembodiments it is preferred to administer daily, in either a single ordivided dose an amount of composition of the invention or dosage formcomprising a composition of the invention which provides from about 100mg to about 1200 mg of mifepristone per day.

The pharmaceutical composition according to the present inventionimproves dissolved mifepristone for absorption of mifepristone in humanbody and enhances bioavailability of the drug in comparison to thecommercially available product (KORLYM®).

The seven or more daily doses of mifepristone can each be administeredby any means suitable, as described in more detail below. In someembodiments, each of the seven or more daily doses of mifepristone areadministered orally. The seven or more daily doses of mifepristone caneach be administered in any suitable dose. For example, the mifepristonecan be administered in an amount of at least about 100 mg. Themifepristone can also be administered in an amount of about 110, 120,130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260,270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400,410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540,550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680,690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820,830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960,970, 980, 990, 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080,1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190 orabout 1200 mg. In some embodiments, the daily dose can be at least 240mg. In some embodiments, the daily dose can be at least 300 mg. In someembodiments, the daily dose can be at least 600 mg. In some embodiments,the daily dose can be at least 480 mg. In some embodiments, the dailydose can be at least 720 mg. In some embodiments, the daily dose can beat least 900 mg. In some embodiments, the daily dose can be at least 960mg. In some embodiments, the daily dose can be at least 1200 mg. Otherdaily doses are useful in the method of the present invention.

The daily doses can be administered for any suitable period of time thatis at least 7 days in length. For example, the daily doses can be for 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, or 28 days. The mifepristone can be administered for longerperiods as required by the patient being treated. In some embodiments,the patient can be treated with 28 or more daily doses over a period of28 or more days.

The mifepristone blood levels can be tested by any means known to one ofskill in the art. For example, the testing can be performed by a plasmasampling collection device suitable for detecting mifepristone serumlevels.

The present invention provides a method for improving efficacy ofmifepristone treatment in a patient suffering from Cushing's syndrome.The method includes treating the patient with seven or more daily dosesof mifepristone over a period of seven or more days; testing the serumlevels of the patient to determine whether the blood levels ofmifepristone are greater than 1631 ng/mL; and adjusting the daily doseof the patient to achieve mifepristone blood levels greater than 1631ng/mL.

The mifepristone blood levels can be at any suitable level to treatCushing's syndrome. For example, the mifepristone blood levels can begreater than about 1400 ng/mL, 1450, 1500, 1550, 1600, 1650, 1700, 1750,1800, 1850, 1900, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800 orgreater than about 2900 ng/mL. In some embodiments, the mifepristoneblood level can be greater than 1450 ng/mL. In some embodiments, themifepristone blood level can be greater than 1469 ng/mL. In someembodiments, the mifepristone blood level can be greater than 1600ng/mL. In some embodiments, the mifepristone blood level can be greaterthan 1631 ng/mL. In some embodiments, the mifepristone blood level canbe greater than 1662 ng/mL. In some embodiments, the mifepristone bloodlevel can be greater than 1666 ng/mL. In some embodiments, themifepristone blood level can be greater than 1700 ng/mL. In someembodiments, the mifepristone blood level can be greater than 1800ng/mL. In some embodiments, the mifepristone blood level can be greaterthan 1820 ng/mL. In some embodiments, the mifepristone blood level canbe greater than 2000 ng/mL. In some embodiments, the mifepristone bloodlevel can be greater than 2022 ng/mL.

The daily dose can be adjusted to any suitable dose to maintain themifepristone blood level above the necessary level. For example, if themifepristone blood level is below 1631 ng/mL, the daily dose can beincreased to 600 mg from 300 mg, to 900 mg from 600 mg, to 900 mg from300 mg, to 1200 mg from 900 mg, to 1200 mg from 600 mg, or to 1200 mgfrom 300 mg. If after another seven daily doses, the mifepristone bloodlevel is still not above the necessary level, the mifepristone daily canagain be increased. For example, the mifepristone daily dose can beincreased to 900 mg from 600 mg, to 1200 mg from 900 mg, or to 1200 mgfrom 600 mg. In some embodiments, the adjusting step comprisesincreasing the daily dose of the patient to achieve mifepristone bloodlevels greater than 1631 ng/mL. Additional adjustments in the dailydoses can be made to maintain the mifepristone blood level above 1631ng/mL.

The daily dose can be adjusted to any suitable dose to maintain themifepristone blood level above the necessary level. For example, if themifepristone blood level is below 1631 ng/mL, the daily dose can beincreased to 480 mg from 240 mg, to 720 mg from 480 mg, to 720 mg from240 mg, to 960 mg from 720 mg, to 960 mg from 480 mg, or to 960 mg from240 mg. If after another seven daily doses, the mifepristone blood levelis still not above the necessary level, the mifepristone daily can againbe increased. For example, the mifepristone daily dose can be increasedto 720 mg from 480 mg, to 960 mg from 720 mg, or to 960 mg from 480 mg.In some embodiments, the adjusting step comprises increasing the dailydose of the patient to achieve mifepristone blood levels greater than1631 ng/mL. Additional adjustments in the daily doses can be made tomaintain the mifepristone blood level above 1631 ng/mL.

In an embodiment, the inventive pharmaceutical composition ofmifepristone is used to control hyperglycemia secondary tohypercortisolism in adult patients with endogenous Cushing's syndromewho have type 2 diabetes mellitus or glucose intolerance and have failedsurgery or are not candidates for surgery.

In other embodiment, the inventive pharmaceutical composition ofmifepristone is used in a regimen with misoprostol, for the medicaltermination of intrauterine pregnancy through 70 days gestation.

As used herein, “to treat” a condition or “treatment” of the conditionis an approach for obtaining beneficial or desired results, such asclinical results. Beneficial or desired results can include, but are notlimited to, alleviation or amelioration of one or more symptoms orconditions; diminishment of extent of disease, disorder, or condition;stabilized (i.e., not worsening) state of disease, disorder, orcondition; preventing spread of disease, disorder, or condition; delayor slowing the progress of the disease, disorder, or condition;amelioration or palliation of the disease, disorder, or condition; andremission (whether partial or total), whether detectable orundetectable. “Palliating” a disease, disorder, or condition means thatthe extent and/or undesirable clinical manifestations of the disease,disorder, or condition are lessened and/or time course of theprogression is slowed or lengthened, as compared to the extent or timecourse in the absence of treatment.

For administration to animal or human subjects, the pharmaceuticalcompositions comprise an effective dosage amount of mifepristone or apharmaceutically acceptable salt thereof. The composition may beprepared using conventional methods, for example, depending on thesubject to be treated, the mode of administration, and the type oftreatment desired (e.g., prevention, prophylaxis, or therapy).

The dosage levels can be dependent on the nature of the condition, drugefficacy, the condition of the patient, the judgment of thepractitioner, and the frequency and mode of administration. The unitdosage forms can be administered to achieve any daily amount describedherein, such as by administering one to five times daily (e.g., one,two, three, four, or five times daily).

Analysis of Samples Withdrawn During In Vitro Dissolution Study

The samples withdrawn from the dissolution study and were analyzed forassay and dissolution release using the following HPLC procedure. Thematerials and general conditions are listed below:

TABLE 1 Chromatographic conditions for in-vitro dissolution and Assayanalysis System HPLC system equipped with UV/PDA detector Column XterraRP18 150 × 4.6 mm, 5 μm Wavelength 250 nm Flow rate 1.0 mL/minuteInjection 10 μL volume Column 40° C. ± 2° C. temperature Sample 25° C. ±2° C. temperature Run time 10 minutes Retention time about 4 to 7minutes Mobile Weigh and transfer 6.8 g of sodium dihydrogen Phase Aphosphate monohydrate into 1000 mL of water and mix to dissolve andobserve the pH 4.50 ± 0.05. If required, adjust with ortho-phosphoricacid or 1N Sodium hydroxide solution, and filter through 0.45μ membranefilter. Mobile Mix 800 mL of acetonitrile and Phase B 200 mL methanoldegas. Mode of Isocratic (Mobile Phase A: Elution Mobile Phase B: 40:60)

TABLE 2 Related substances identification by HPLC Chromatographicconditions System HPLC system equipped with UV/PDA detector ColumnXterra RP18 150 × 4.6 mm, 5 μm Wavelength 250 nm Flow rate 1.0 mL/minuteInjection 10 μL volume Column 40° C. ± 2° C. temperature Sample 25° C. ±2° C. temperature Run time 30 minutes Retention time about 13 to 14minutes Mobile Weigh and transfer 6.8 g of sodium dihydrogen Phase Aphosphate monohydrate into 1000 mL of water and mix to dissolve andobserve the pH 4.50 ± 0.05. If required, adjust with ortho-phosphoricacid or 1N Sodium hydroxide solution, and filter through 0.45μ membranefilter. Mobile Mix 800 mL of acetonitrile and Phase B 200 mL methanoldegas. Mode of Gradient Elution

TABLE 3 Gradient program Time (min) % Mobile phase-A % Mobile phase-B0.01 60 40 5 50 50 10 50 50 15 10 90 20 10 90 25 60 40 30 60 40

EXAMPLES

The following examples are exemplary and not intended to be limiting.The above disclosure provides many different embodiments forimplementing the features of the invention, and the following examplesdescribe certain embodiments. It will be appreciated that othermodifications and methods known to one of ordinary skill in the art canalso be applied to the following experimental procedures, withoutdeparting from the scope of the invention.

Example 1

TABLE 4 Quantitative formula for mifepristone nano-suspension (mg/unit)Compositions of Mifepristone nano-suspension Composition CompositionComposition Composition Ingredients A B C D Batch size 250 tablets 750tablets 250 tablets 250 tablets Mifepristone 300 mg 300 mg 300 mg 300 mgHPMC 25 mg 25 mg 25 mg 25 mg (METHOCEL ® E5 LV) HPMC — — — 8.0 mg(METHOCEL ® E3 LV) Sodium lauryl 8 mg 8 mg 8 mg — sulphate (KOLLIPHOR ®SLS) Docusate sodium 1 mg 1 mg 1 mg 1 mg Purified water Q.S. Q.S. Q.S.Q.S. Milling parameters Chamber capacity 200.00 mL 200.00 mL 200.00 mL200.00 mL Zirconium 0.3 mm 0.3 mm 0.2 mm 0.3 mm beads size Agitatorspeed 1750 2500 2500 2500Manufacturing Procedure of Composition A, B, C and D:

Compositions A, B, C and D were manufactured according to the followingprocedure:

-   a) Specified amount of purified water was taken in a suitable    container and added specified quantity of docusate sodium under    continuous stirring to obtain a solution.-   b) Sodium Lauryl Sulphate (KOLLIPHOR® SLS Fine) was added to the    step (a) solution and stirred continuously to obtain a solution.-   c) HPMC (METHOCEL® E5 LV/METHOCEL® E3 LV) was added to the step (b)    solution and stirred continuously to obtain a solution.-   d) Mifepristone was added to the step (c) solution and stirred for 5    minutes to obtain mifepristone dispersion.-   e) Homogenized the above mifepristone dispersion using IKA's Ultra    TURRAX® homogenizer at 1000 RPM for 15 minutes.-   f) The above homogenized mifepristone slurry was nano-sized in    ball-mill chamber to obtain a nano-suspension containing the desired    particle size of mifepristone. The particle size distribution was    measured using a Mastersizer 3000 particle analyser.    Particle Size Distribution of Mifepristone in Composition A:

Homogenized mifepristone slurry of Composition A was ball-milled at aspeed of 1730 RPM at 30° C. for 80 minutes and further milled at 10° C.for 70 minutes, using the conditions set forth in Tables 5 and 6.

TABLE 5 At the Input temperature of 30° C.: Running Time (minutes)Initial 15 30 45 60 80 Agitator Speed (RPM) 1750 1730 1730 1730 17301730 Temperature In (° C.) 30 30 30 30 30 30 Temperature Out (° C.) 3236 36 36 36 36 Particle size distribution (in microns) D10 0.564 0.390.344 0.322 0.3 0.287 D50 1.6 0.63 0.5 0.451 0.424 0.404 D90 3.67 1.880.825 0.64 0.592 0.561

TABLE 6 At the Input temperature of 10° C.: Running Time (minutes)Initial 20 40 70 Agitator Speed (RPM) — 1750 1750 1750 Temperature In (°C.) — 10 10 10 Temperature Out (° C.) — 22 22 22 Particle sizedistribution (in microns) D10 0.284 0.268 0.261 0.250 D50 0.404 0.380.37 0.357 D90 0.57  0.522 0.511 0.495Particle Size Distribution of Mifepristone in Composition B:

Homogenized mifepristone slurry of Composition B was ball-milled atspeed of 2500 RPM at 20° C. for 140 minutes (see Table 7). TheComposition B was stored for a period of 15 days. No significant changein particle size distribution was observed during the 15 days storageperiod.

TABLE 7 Running Time (minutes) Initial 20 40 60 80 100 120 140 Agitatorspeed (RPM) — 2500 2500 2500 2500 2500 2500 2500 Temperature In (° C.) —20 20 20 20 20 20 20 Temperature Out (° C.) — 25 25 25 25 25 25 25Particle size distribution (in microns) D10 0.578 0.435 0.376 0.3470.322 0.304 0.287 0.284 D50 1.58 0.809 0.577 0.508 0.454 0.429 0.4050.397 D90 4.07 2.74 1.72 0.949 0.648 0.601 0.569 0.549Particle Size Distribution of Mifepristone in Composition C:

Homogenized mifepristone slurry of Composition C was ball-milled atspeed of 2500 RPM at 20° C. for 100 minutes with 0.2 mm zirconium beads(see Table 8). Change in zirconium beads size from 0.3 mm to 0.2 mm inmilling procedure does not have any significant effect on the particlesize distribution of the final nano-suspension.

TABLE 8 Running Time (minutes) Initial 20 40 60 80 100 Agitator Speed(RPM) — 2500 2500 2500 2500 2500 Temperature In (° C.) — 20 20 20 20 20Temperature Out (° C.) — 24 26 26 26 26 Particle size distribution (inmicrons) D10 0.61 0.397 0.341 0.311 0.293 0.276 D50 1.8 0.667 0.5040.439 0.415 0.391 D90 4.56 2.63 1.31 0.627 0.582 0.553Particle Size Distribution of Mifepristone in Composition D:

Homogenized mifepristone slurry of Composition D was ball-milled atspeed of 1754 RPM at 20° C. for 15 minutes and further at a speed of2500 RPM at 20° C. for an additional 60 minutes (see Table 9). Change ina viscosity grade of HPMC from METHOCEL® E5 LV to METHOCEL® E3 LV wasfound to have no effect on the particle size distribution of the finalnano-suspension.

TABLE 9 Running Time (minutes) Initial 15 30 45 60 75 Agitator Speed(RPM) — 1754 2500 2500 2500 2500 Temperature In (° C.) — 20 20 20 20 20Temperature Out (° C.) — 24 26 26 26 26 Particle size distribution (inmicrons) D10 0.548 0.392 0.326 0.311 0.295 0.281 D50 1.5 0.622 0.4630.439 0.419 0.397 D90 3.92 1.9 0.668 0.627 0.588 0.559

Example 2

TABLE 10 Quantitative formula for mifepristone nano-suspension(mg/unit). Compositions of Mifepristone nano-suspension IngredientsComposition E Composition F Batch size 250 tablets 250 tabletsMifepristone 300 mg 300 mg HPMC 25 mg 25 mg (METHOCEL ® E5 LV) SodiumLauryl 10 mg — Sulphate (KOLLIPHOR ® SLS) Poloxamer 188 4 mg —Polysorbate 80 — 4 mg (TWEEN ® 80) Purified Water Q.S. Q.S. Millingparameters Chamber Capacity 200.00 mL 200.00 mL Zirconium 0.3 mm 0.3 mmbeads size Agitator Speed 1750 2500Manufacturing Procedure of Composition E:

Composition E was manufactured according to the following procedure:

-   a) Required amount of purified water was taken in a suitable    container and specified quantity of Poloxamer 188 was added and    stirred continuously to obtain a solution.-   b) Sodium lauryl sulphate (KOLLIPHOR® SLS Fine) was added to the    step (a) solution and stirred continuously to obtain a solution.-   c) Hydroxypropyl methyl cellulose (METHOCEL® E5 LV/METHOCEL® E3 LV)    was added to the step (b) solution under stirring and stirred    continuously to obtain a solution.-   d) Mifepristone was added to the step (c) solution and stirred for 5    minutes to obtain Mifepristone dispersion.-   e) Mifepristone dispersion was homogenised using IKA's Ultra Turrax    homogenizer at 1000 RPM for 15 minutes.-   f) The above homogenized mifepristone slurry was nano-sized in    ball-mill chamber to obtain nano-suspension containing desired    particle size of mifepristone. The particle size distribution was    measured by using Mastersizer 3000 particle analyser.    Manufacturing Procedure of Composition F:

Composition F was manufactured according to the following procedure:

-   a) Specified amount of purified water was taken in a suitable    container and specified quantity of TWEEN® 80 was added and stirred    continuously to obtain a solution.-   b) Hydroxypropyl methyl cellulose (METHOCEL® E5 LV) was added to the    step (a) solution and stirred continuously to obtain a solution.-   c) Mifepristone was added to the step (b) solution and stirred for 5    minutes to obtain mifepristone dispersion.-   d) Mifepristone dispersion was homogenized using IKA's Ultra TURRAX®    homogenizer at 1000 RPM for 15 minutes.-   e) The above homogenized mifepristone slurry was nano-sized in    ball-mill chamber to obtain nano-suspension containing desired    particle size of mifepristone. The particle size distribution was    measured by using Mastersizer 3000 particle analyser.    Particle Size Distribution of Mifepristone in Composition E:

Homogenized mifepristone slurry of Composition E was ball-milled atspeed of 1759 RPM at 8.5° C. for 35 minutes. It was observed that duringthe milling process Poloxamer 188 increases the particles agglomerationand the process was discontinued.

TABLE 11 Running Time (minutes) Initial 5 15 35 Agitator Speed (RPM) —1759 1759 1759 Temperature In (° C.) — 8.5 8.5 8.5 Temperature Out (°C.) — 26 26 26 Particle size distribution D10 (in microns)  0.578 0.9980.833 1.76 D50 (in microns) 1.54 25.3 28.5 24 D90 (in microns) 3.59 51.7217 47.5Particle Size Distribution of Mifepristone in Composition F:

TABLE 12 Homogenized mifepristone slurry of Composition F was ball-milled at speed of 2500 RPM at 20° C. for 100 minutes. Running Time(minutes) Initial 20 40 60 80 100 Agitator Speed (RPM) — 2500 2500 25002500 2500 Temperature In (° C.) — 20 20 20 20 20 Temperature Out (° C.)— 25 25 25 25 25 Particle size distribution (in microns) D10 0.638 0.3820.333 0.314 0.298 0.28 D50 1.76 0.599 0.49 0.444 0.423 0.398 D90 4.481.97 1.09 0.639 0.596 0.563

TABLE 13 The mifepristone nano-suspension was subjected to stability of2 days. Particle size distribution (in microns) Particle Size InitialDistribution Initial (after milling for (in microns) (before milling)100 minutes) Day 2 D10 0.638 0.28 0.382 D50 1.76 0.398 0.599 D90 4.480.563 1.97

It was observed that particle size increased within 2 days andsuspension was found to be unstable.

Example 3

TABLE 14 Composition of mifepristone tablet 240 mg Composition GIngredients mg/unit Mifepristone nano-suspension Mifepristone 240.00HPMC (METHOCEL ® E5 LV) 20.00 Sodium lauryl sulphate (KOLLIPHOR ® SLS)6.40 Docusate sodium 0.80 Purified water Q.S. Intra-granular materialSilicified microcrystalline cellulose (PROSOLV ® SMCC 90) 280.40 Sodiumstarch glycolate (PRIMOJEL ®) 27.20 Extra-granular materialMicrocrystalline cellulose (CEOLUS ® KG-802) 121.40 Sodium starchglycolate (PRIMOJEL ®) 20.40 Magnesium Stearate (LIGAMED ® MF-2-V) 3.40Core tablet weight (mg) 720.00 Film-coating blend OPADRY ® II CompleteFilm Coating 21.60 System 85F18422 white Purified Water Q.S. CoatedTablet Weight (mg) 741.60Manufacturing Procedure of Composition G:

Composition G was manufactured according to the following procedure:

-   a) Specified amount of purified water was taken in a suitable    container and specified quantity of docusate sodium was added and    stirred continuously to obtain a solution.-   b) Sodium lauryl sulphate was added to the step (a) solution and    stirred continuously to obtain a solution.-   c) Hydroxypropyl methyl cellulose was added to the step (b) solution    and stirred continuously to obtain a solution.-   d) Mifepristone was added to the step (c) solution and stirred for 5    minutes to obtain Mifepristone dispersion.-   e) Mifepristone dispersion was homogenized using IKA's Ultra TURRAX®    homogenizer at 1000 RPM for 15 minutes.-   f) The above homogenized mifepristone slurry was nano-sized in    ball-mill chamber to obtain nano-suspension containing desired    particle size of mifepristone. The particle size distribution was    measured by using Mastersizer 3000 particle analyser.-   g) Specified quantities of the silicified microcrystalline cellulose    and sodium starch glycolate were dispensed in a bowl and warmed to    reach 28° C. to 30° C. temperature.-   h) The nano-sized mifepristone suspension according to step (f) was    sprayed onto the warmed intra-granular material according to step    (g). The sprayed granules were dried at a temperature of 50° C. to    65° C. and sieved through 30 number mesh sieve.-   i) Dispensed the specified quantities of milled granules of step    (h), sodium starch glycolate, microcrystalline cellulose, and    magnesium stearate and compressed using tablet compression machine.    The tablets according to step (i) were coated with suitable coating    materials.

Example 4

TABLE 15 Composition of mifepristone tablet 240 mg Composition HIngredients mg/unit Mifepristone nano-suspension Mifepristone 240.00HPMC 20.00 Sodium lauryl sulphate 6.40 Docusate sodium 0.80 Purifiedwater Q.S. Intra-granular material Silicified microcrystalline cellulose280.40 Sodium starch glycolate 27.20 Extra-granular materialMicrocrystalline cellulose 119.6 Sodium starch glycolate 20.40 Colloidalsilicon dioxide 1.8 Magnesium Stearate 3.40 Core tablet weight (mg)720.00 Film-coating blend OPADRY ® II Complete Film Coating 21.60 System85F18422 white Purified Water Q.S. Coated Tablet Weight (mg) 741.60Manufacturing Procedure of Composition H:

Composition H was manufactured according to the following procedure:

-   a) Specified amount of purified water was taken in a suitable    container and specified quantity of docusate sodium was added and    stirred continuously to obtain a solution.-   b) Sodium lauryl sulphate was added to the step (a) solution and    stirred continuously to obtain a solution.-   c) Hydroxypropyl methyl cellulose was added to the step (b) solution    and stirred continuously to obtain a solution.-   d) Mifepristone was added to the step (c) solution and stirred for 5    minutes to obtain Mifepristone dispersion.-   e) Mifepristone dispersion was homogenized using IKA's Ultra TURRAX®    homogenizer at 1000 RPM for 15 minutes.-   f) The above homogenized mifepristone slurry was nano-sized in    ball-mill chamber to obtain nano-suspension containing desired    particle size of mifepristone. The particle size distribution was    measured by using Mastersizer 3000 particle analyser.-   g) Specified quantities of the silicified microcrystalline cellulose    and sodium starch glycolate were dispensed in a bowl and warmed to    reach 28° C. to 30° C. temperature.-   h) The nano-sized mifepristone suspension according to step (f) was    sprayed onto the warmed intra-granular material according to step    (g). The sprayed granules were dried at a temperature of 50° C. to    65° C. and sieved through 30 number mesh sieve.-   i) Specified quantities of milled granules of step (h), sodium    starch glycolate, microcrystalline cellulose, colloidal silicon    dioxide and magnesium stearate were blended and compressed using    tablet compression machine. The tablets according to step (i) were    coated with suitable coating materials.

Example 5

Particle Size Distribution of Mifepristone Nano-Suspensions Used inComposition G and H:

TABLE 16 Process parameters of nano-milling for preparation ofmifepristone nano-suspensions used in composition G and H:Nano-suspension Nano-suspension used in used in Parameters composition Gcomposition H Mifepristone slurry 20% 20% initial solid content Afterrinsing of container 15% 15.8%   bottle and mill Due to additional NA14.1%   0.1 mm beads rinsing Size of beads used  0.3 mm 0.3 mm and 0.1mm Screen 0.13 mm 0.13 mm and 0.03 mm Occupancy 65% 65% Nano millingtime 90 minutes with 0.3 60 minutes with 0.3 mm beads mm beads and 80minutes with 0.1 mm beads Particle Size Distribution (PSD) ofmifepristone (in microns) D10 0.090 0.0602 D50 0.186 0.122 D90 0.3690.233

TABLE 17 Effect of storage time on particle size distribution ofmifepristone in composition G Particle Size Distribution (PSD) (inmicrons) PSD Initial Day 1 Day 3 Day 7 Day 15 D10 0.284 0.288 0.2700.267 0.277 D50 0.397 0.404 0.396 0.394 0.404 D90 0.549 0.561 0.5830.584 0.597

Example 6

A study was conducted to test the pharmacokinetics and bioavailabilityof Composition G and H in healthy adult, human volunteers, under fedstate.

This study is open label, balanced, randomized, single-dose,three-treatment, three-sequence, three-period, crossover, oralbioavailability study of Mifepristone tablet 240 mg (Composition G and H(Test products=T); Dose: 4 tablets×240 mg=960 mg) and KORLYM®(Mifepristone tablets 300 mg (Reference product=R); Dose: 4 tablets x300 mg=1200 mg) in 11 healthy, adult, male and postmenopausal femalehuman subjects under fed condition (n=11).

TABLE 18 Composition G KORLYM ® Dose: Dose: 90% Pharmaco- 960 mg 1200 mgConfidence kinetic (Fed) = T (Fed) = R T/R interval (CI) ParametersLeast Square Geometric Mean Ratio (Lower-Upper) Analyte: MifepristoneC_(max) (ng/mL) 4060.8 4197.7649 96.74 85.17-109.9 AUC_(0-72 h) 103748.3108957.73 95.22 88.63-102.3 (ng · hr/mL) Analyte: N-mono-demethylatedRU42633 C_(max) (ng/mL) 2530.4682 2727.18 92.79  85.89-100.24AUC_(0-72 h) 126139.23 128855 97.89  90.67-105.69 (ng · hr/mL) Analyte:Hydroxylated RU42698 C_(max) (ng/mL) 605.5 665.4428 90.99 83.35-99.33AUC_(0-72 h) 31392.1 32669.123 96.09 89.39-103.3 (ng · hr/mL)

TABLE 19 Composition H KORLYM ® Dose: Dose: 90% Pharmaco- 960 mg 1200 mgConfidence kinetic (Fed) = T (Fed) = R T/R interval (CI) ParametersLeast Square Geometric Mean Ratio (Lower-Upper) Analyte: MifepristoneC_(max) (ng/mL) 4615.0 4197.7649 109.94 99.38-121.6 AUC_(0-72 h)117713.9 108957.73 108.04  93.6-124.7 (ng · hr/mL) Analyte:N-mono-demethylated RU42633 C_(max) (ng/mL) 2809.9 2727.1793 103.0393.22-113.9 AUC_(0-72 h) 139504.4 128854.68 108.26 93.63-125.2 (ng ·hr/mL) Analyte: Hydroxylated RU42698 C_(max) (ng/mL) 664.80 665.44 99.90 86.71-115.11 AUC_(0-72 h) 34963.44 34963.44 107.02  93.65-122.30 (ng ·hr/mL)

Example 7

Dissolution Profiles of Composition G and H:

TABLE 20 Dissolution conditions: Apparatus USP Type-2 (Paddle)Dissolution Media pH 1.8 potassium chloride buffer Media Volume 900 mLTemperature 37.0° C. ± 0.5° C. Agitation speed 50 RPM Sampling Timepoint5, 10, 15, 30, 45, and 60 minutes Sample Volume 10 mL Replacement Volume10 mL Filters 10μ full flow filter

TABLE 21 Assay, drug release and related substance profile: KORLYM ® 300mg tablet Composition G Composition H Storage condition; duration Time25° C./ 40° C./ 25° C./ 40° C./ Points 25° C./ 60% RH; 75% RH; 60% RH;75% RH; (minutes) 60% RH Initial 6 M* 6 M Initial 3 M* 3 M 5 36 90 88 8696 90 90 10 77 91 89 88 97 91 91 15 88 92 90 88 97 92 92 30 94 92 91 8998 93 93 45 95 92 91 90 99 94 93 60 96 93 92 90 99 94 94 Assay (%) ofMifepristone % NA 100 99.8 100.7 104.1 101.8 102.6 Water contentmeasured by Karl Fisher (KF) % NA 4.1 3.3 3.3 2.4 3.7 3.7 Relatedsubstance (%) RS-A* NA 0.39 0.49 0.52 0.48 0.48 0.51 Any NA 0.05 0.040.06 0.04 0.04 0.04 single impurity Total NA 0.65 0.70 0.79 0.80 0.770.80 impurities *6 M = 6 months; 3 M = 3 months; RS-A = N-Demethylmifepristone impurity; NA = Not Analyzed or Not Applicable.

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that it can be performed within awide equivalent range of parameters without affecting the scope of theinvention or any embodiment thereof. All publications, patentapplications and patents disclosed herein are incorporated by referencein their entirety.

What is claimed:
 1. An oral pharmaceutical composition comprising:nanosized mifepristone particles and one or more other pharmaceuticallyacceptable excipients; wherein the nanosized mifepristone particlescomprise: (a) a therapeutically effective amount of surface stabilizedmifepristone particles; (b) at least one suspension-aid; (c) at leastone surfactant; (d) at least one surface stabilizer; and (e) optionally,one or more other pharmaceutically acceptable excipients; wherein saidsurface stabilized mifepristone particles have an average D90 particlesize less than 1000 nm; wherein said pharmaceutical composition is animmediate release pharmaceutical composition suitable for oraladministration, and comprises 220 mg to 1200 mg of mifepristone in asingle oral dose; wherein said pharmaceutical composition provides anin-vitro mifepristone release of not less than about 70 wt % of themifepristone, within 45 minutes of dissolution in a 900 mL pH 1.8potassium chloride dissolution medium, measured using USP Apparatus II,at 50 RPM and 37 ° C.
 2. The oral pharmaceutical composition accordingto claim 1, wherein the at least one suspension-aid is selected from thegroup consisting of hydroxypropyl methyl cellulose acetate succinate(HPMC-AS), polyvinyl pyrrolidine and vinyl acetate (PVP/VA) copolymer,hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), hydroxypropylcellulose (HPC), carboxymethyl cellulose (CMC), polyvinyl pyrrolidine(PVP), and mixtures thereof.
 3. The oral pharmaceutical compositionaccording to claim 1, wherein the at least one surfactant is sodiumlauryl sulphate.
 4. The oral pharmaceutical composition according toclaim 1, wherein the at least one surface stabilizer is docusate sodium.5. The oral pharmaceutical composition according to claim 1, wherein aweight ratio of the surface stabilized mifepristone particles to the atleast one suspension-aid is from about 20:1 to about 1:20.
 6. The oralpharmaceutical composition according to claim 1, wherein a weight ratioof the surface stabilized mifepristone particles to the at least onesurfactant is from about 50:1 to about 1:50.
 7. The oral pharmaceuticalcomposition according to claim 1, wherein the surface stabilizedmifepristone particles comprise the at least one surface stabilizer inan amount from about 0.05% w/w to about 1% w/w of a total weight of thepharmaceutical composition.
 8. The oral pharmaceutical compositionaccording to claim 1, in the form of a tablet or capsule comprises: (a)at least one intra-granular material, (b) at least one extra-granularmaterial, and (c) optionally, a coating.
 9. The oral pharmaceuticalcomposition according to claim 8, wherein the at least oneintra-granular material is prepared by mixing or spraying anano-suspension of mifepristone particles over the intra-granularmaterial.
 10. The oral pharmaceutical composition according to claim 9,wherein the nano-suspension of mifepristone particles comprises:mifepristone, hydroxypropyl methylcellulose (HPMC), sodium laurylsulphate, docusate sodium, and purified water.
 11. The oralpharmaceutical composition according to claim 8, wherein theintra-granular material and the extra-granular material are selectedfrom the group consisting of diluents, binders, disintegrants,lubricants, glidants, surfactants, plasticizers, solubilizers,antioxidants and mixtures thereof.
 12. The oral pharmaceuticalcomposition according to claim 8, wherein (a) the at least oneintra-granular material is selected from the group consisting ofsilicified microcrystalline cellulose, sodium starch glycolate, andmixtures thereof, and (b) the least one extra-granular material isselected from the group consisting of microcrystalline cellulose, sodiumstarch glycolate, colloidal silicon dioxide, magnesium stearate, andmixtures thereof.
 13. The oral pharmaceutical composition according toclaim 1, wherein said composition exhibits at least about 15% enhancedbioavailability in the fed state, compared to a drug productcorresponding to a reference composition having the same dosage.
 14. Theoral pharmaceutical composition according to claim 1, wherein saidcomposition upon oral administration in fed state exhibitsbioequivalence to a drug product corresponding to a referencecomposition, in the fed state, and wherein said bioequivalence isestablished by at least one of: (i) a confidence interval for leastsquare geometric mean of AUC_(0-t) between about 80% and about 125%;(ii) a confidence interval for least square geometric mean ofAUC_(0-infinity) between about 80% and about 125%; or (iii) a confidenceinterval for least square geometric mean of C_(max) between about 80%and about 125% or combinations thereof.
 15. The oral pharmaceuticalcomposition according to claim 1, having a level of(11β-[4-(methylamino) phenyl]-17-hydroxy-17α-(1-propynyl)estra-4,9-dien-3-one) impurity that is less than about 1% (w/w) asmeasured by HPLC, when stored at 25° C/60% RH for at least 3 months. 16.The oral pharmaceutical composition according to claim 1, having a levelof total related substances of mifepristone less than about 2% (w/w) asmeasured by HPLC, when stored at 25° C/60% RH for at least 3 months. 17.The oral pharmaceutical composition according to claim 1, comprising 240mg to 280 mg of mifepristone in a single oral dose.
 18. The oralpharmaceutical composition according to claim 1, comprising 250 mg ofmifepristone in a single oral dose.
 19. An oral pharmaceuticalcomposition comprising: nanosized mifepristone particles and one or moreother pharmaceutically acceptable excipients; wherein the nanosizedmifepristone particles comprise: (a) a therapeutically effective amountof mifepristone; (b) at least one suspension-aid; (c) at least onesurfactant; (d) at least one surface stabilizer; and (e) optionally, oneor more other pharmaceutically acceptable excipients; wherein the atleast one surfactant is sodium lauryl sulphate; wherein the at least onesurface stabilizer is docusate sodium; wherein said nanosizedmifepristone particles have an average D90 particle size less than 1000nm; wherein said pharmaceutical composition is an immediate releasepharmaceutical composition suitable for oral administration, andcomprises 220 mg to 1200 mg of mifepristone in a single oral dose;wherein said pharmaceutical composition provides an in-vitromifepristone release of not less than about 70 wt % of the mifepristone,within 45 minutes of dissolution in a 900 mL pH 1.8 potassium chloridedissolution medium, measured using USP Apparatus II, at 50 RPM and 37 °C.
 20. The oral pharmaceutical composition according to claim 19,comprising 240 mg to 280 mg of mifepristone in a single oral dose. 21.The oral pharmaceutical composition according to claim 19, comprising250 mg of mifepristone in a single oral dose.
 22. The oralpharmaceutical composition according to claim 19, wherein the at leastone suspension-aid is selected from the group consisting ofhydroxypropyl methyl cellulose acetate succinate (HPMC-AS), polyvinylpyrrolidine and vinyl acetate (PVP/VA) copolymer, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC),polyethylene glycol (PEG), hydroxypropyl cellulose (HPC), carboxymethylcellulose (CMC), polyvinyl pyrrolidine (PVP), and mixtures thereof. 23.The oral pharmaceutical composition according to claim 19, wherein aweight ratio of the nanosized mifepristone particles to thesuspension-aid is from about 20:1 to about 1:20.
 24. The oralpharmaceutical composition according to claim 19, wherein a weight ratioof the nanosized mifepristone particles to the at least one surfactantis from about 50:1 to about 1:50.
 25. The oral pharmaceuticalcomposition according to claim 19, in the form of a tablet or capsulecomprises: (a) at least one intra-granular material, (b) at least oneextra-granular material, and (c) optionally, a coating.
 26. The oralpharmaceutical composition according to claim 25, wherein the at leastone intra-granular material is prepared by mixing or spraying a nano-suspension of mifepristone particles over the intra-granular material.27. The oral pharmaceutical composition according to claim 26, whereinthe nano-suspension of mifepristone particles comprises: mifepristone,hydroxypropyl methylcellulose (HPMC), sodium lauryl sulphate, docusatesodium, and purified water.
 28. The oral pharmaceutical compositionaccording to claim 25, wherein the intra-granular material and theextra-granular material are selected from the group consisting ofdiluents, binders, disintegrants, lubricants, glidants, surfactants,plasticizers, solubilizers, surface stabilizers, antioxidants andmixtures thereof.
 29. The oral pharmaceutical composition according toclaim 25, wherein (a) the at least one intra-granular material isselected from the group consisting of silicified microcrystallinecellulose, sodium starch glycolate, and mixtures thereof, and (b) theleast one extra-granular material is selected from the group consistingof microcrystalline cellulose, sodium starch glycolate, colloidalsilicon dioxide, magnesium stearate, and mixtures thereof.